EP2852605A1 - Promédicaments de 3',5'-phosphate cyclique pour traiter une infection par le virus de l'hépatite c - Google Patents

Promédicaments de 3',5'-phosphate cyclique pour traiter une infection par le virus de l'hépatite c

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Publication number
EP2852605A1
EP2852605A1 EP13725544.4A EP13725544A EP2852605A1 EP 2852605 A1 EP2852605 A1 EP 2852605A1 EP 13725544 A EP13725544 A EP 13725544A EP 2852605 A1 EP2852605 A1 EP 2852605A1
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Prior art keywords
independently
compound
certain embodiments
range
integer selected
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EP13725544.4A
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German (de)
English (en)
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EP2852605B1 (fr
Inventor
Christophe Claude Parsy
Francois-Rene Alexandre
Cyril B. Dousson
David Dukhan
Gilles Gosselin
Houcine Rahali
Dominique Surleraux
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Centre National de la Recherche Scientifique CNRS
Universite de Montpellier I
Idenix Pharmaceuticals LLC
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Centre National de la Recherche Scientifique CNRS
Universite Montpellier 2 Sciences et Techniques
Idenix Pharmaceuticals LLC
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals
    • C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
    • C07H19/11—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids containing cyclic phosphate
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals
    • C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
    • C07H19/213—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids containing cyclic phosphate

Definitions

  • 3 ',5 '-cyclic phosphate prodrug nucleotides are provided which display remarkable efficacy and bioavailability for the treatment of, for example, HCV infection in a human.
  • HCV hepatitis C virus
  • HCV causes a slow growing viral infection and is the major cause of cirrhosis and hepatocellular carcinoma (Di Besceglie, A. M. and Bacon, B. R., Scientific American, Oct.: 80-85, 1999; Boyer, N. et al., J. Hepatol. 32:98- 112, 2000). It is estimated there are about 130-170 million people with chronic hepatitis C virus infection, and there are about 350,000 deaths from hepatitis C-related liver diseases each year (Hepatitis C Fact Sheet, World Health Organization Fact Sheet No. 164, June 2011). Cirrhosis caused by chronic hepatitis C infection accounts for 8,000-12,000 deaths per year in the United States, and HCV infection is the leading indication for liver transplantation.
  • HCV infection becomes chronic in about 75% of cases, with many patients initially being asymptomatic.
  • the first symptoms of HCV infection are often those of chronic liver disease.
  • About 20 to 30% of patients with chronic hepatitis due to HCV develop cirrhosis, although this may take decades.
  • Development of cirrhosis due to HCV also increases the risk of hepatocellular cancer (The Merck Manual Online, Chronic Hepatitis, available at www.merckmanuals.com/professional/hepatic_and_biliary_disorders/hepatitis/chronic_ hepatitis.html, last revision February 2007).
  • the compounds are 3 ',5 '-cyclic phosphate prodrugs.
  • the 3 ',5 '-cyclic phosphate prodrugs display remarkable efficacy or bioavailability, or both, for the treatment of, for example, HCV infection in a human.
  • the compounds provided herein are useful in the prevention and treatment of Flaviviridae infections and other related conditions such as anti- Flaviviridae antibody positive and Flaviviridae-positivQ conditions, chronic liver inflammation caused by HCV, cirrhosis, fibrosis, acute hepatitis, fulminant hepatitis, chronic persistent hepatitis, and fatigue.
  • These compounds or formulations can also be used prophylactically to prevent or retard the progression of clinical illness in individuals who are anti-Flaviviridae antibody or Flaviviridae-antigen positive or who have been exposed to a Flaviviridae.
  • the Flaviviridae is hepatitis C.
  • the compounds are used to treat any virus that replicates through an RNA-dependent R A polymerase.
  • a method for the treatment of a Flaviviridae infection in a host including a human, includes administering an effective amount of a compound provided herein, administered either alone or in combination or alternation with another anti- Flaviviridae agent, optionally in a pharmaceutically acceptable carrier.
  • each h E is independently alkyl, substituted alkyl, aryl, or heteroaryl
  • each Ar is independently an arylene or heteroarylene
  • each L is independently alkylene or substituted alkylene
  • each R is independently hydrogen, alkyl, substituted alkyl, aryl, or heteroaryl
  • each R A is independently a carbocyclic or heterocyclic ring
  • each p is independently 0 or 1.
  • each X is independently alkoxyl, hydrogen, or hydroxyl
  • each Y is independently hydroxyl, acetoxyl, or fluoro
  • each Z is independently - LC(0)0(L) p CR 3 , -L-Ar-C(0)0(L) p CR 3 , -CR(E)(L) p OC(0)0(L) p CR 3 , -LSC(0)LOH, - LSC(0)LOC(0)(L) p CR 3 , -LSC(0)LOC(0)(L) p NR 2 , -LS-S(L) p CR 3 ,-LS-SLOH, -
  • each B is independently an alkyl group substituted with aminocarboxylene, carboxylene, or both; each D is independently each E is independently alkyl, substituted alkyl, aryl, or heteroaryl; each Ar is independently an arylene or heteroarylene; each L is independently alkylene or substituted alkylene; each R is independently hydrogen, alkyl, substituted alkyl, aryl, or heteroaryl; each R A is independently a carbocyclic or heterocyclic ring; and each p is independently 0 or 1.
  • the compounds provided herein are provided or administered in combination with a second therapeutic agent, such as one useful for the treatment or prevention of HCV infections.
  • a second therapeutic agent such as one useful for the treatment or prevention of HCV infections.
  • Exemplary second therapeutic agents are provided in detail elsewhere herein.
  • compositions, single unit dosage forms, and kits suitable for use in treating or preventing disorders such as HCV infections which comprise a therapeutically or prophylactically effective amount of a compound provided herein, e.g., of Formula I, and a therapeutically or prophylactically effective amount of a second therapeutic agent such as one useful for the treatment or prevention of HCV infections.
  • a method of treatment of a liver disorder comprising administering to an individual in need thereof a treatment effective amount of a 3 ',5 '-cyclic phosphate prodrug compound.
  • Flaviviridae which can be treated are, e.g., discussed generally in Fields Virology, Fifth Ed., Editors: Knipe, D. M., and Howley, P. M., Lippincott Williams & Wilkins
  • the Flaviviridae is HCV.
  • the Flaviviridae is a flavivirus or pestivirus.
  • the Flaviviridae can be from any class of Flaviviridae.
  • the Flaviviridae is a mammalian tick-borne virus.
  • the Flaviviridae is a seabird tick-borne virus.
  • the Flaviviridae is a mosquito-borne virus.
  • the Flaviviridae is an Aroa virus.
  • the Flaviviridae is a Dengue virus.
  • certain embodiments are a mammalian tick-borne virus.
  • the Flaviviridae is a seabird tick-borne virus.
  • the Flaviviridae is a mosquito-borne virus.
  • the Flaviviridae is an Aroa virus.
  • the Flaviviridae is a Dengue virus.
  • the Flaviviridae is a Japanese encephalitis virus. In certain embodiments, the Flaviviridae is a Kokobera virus. In certain embodiments, the Flaviviridae is a Ntaya virus. In certain embodiments, the Flaviviridae is a Spondweni virus. In certain embodiments, the Flaviviridae is a Yellow fever virus. In certain embodiments, the Flaviviridae is a Entebbe virus. In certain embodiments, the Flaviviridae is a Modoc virus. In certain embodiments, the Flaviviridae is a Rio Bravo virus.
  • flaviviruses include, without limitation: Absettarov, Aedes, Alfuy, Alkhurma, aba, Aroa, Bagaza, Banzi, Bukalasa bat, Bouboui, Bussuquara, Cacipacore, Calbertado, Carey Island, Cell fusing agent, Cowbone Ridge, Culex, Dakar bat, Dengue 1, Dengue 2, Dengue 3, Dengue 4, Edge Hill, Entebbe bat, Gadgets Gully, Hanzalova, Hypr, Ilheus, Israel turkey meningoencephalitis, Japanese encephalitis, Jugra, Jutiapa, Kadam, Kamiti River, Karshi, Kedougou, Kokobera, Koutango, Kumlinge, Kunjin, Kyasanur Forest disease, Langat, Louping ill, Meaban, Modoc, Montana myotis leukoencephalitis, Murray valley encephalitis, Nakiwogo, Naranjal, Negishi, Nt
  • Pestiviruses which can be treated are discussed generally in Fields Virology, Fifth Ed., Editors: Knipe, D. M., and Howley, P. M., Lippincott Williams & Wilkins Publishers, Philadelphia, PA, Chapters 33-35, 2006.
  • Specific pestiviruses include, without limitation: bovine viral diarrhea virus (“BVDV”), classical swine fever virus (“CSFV,” also called hog cholera virus), and border disease virus (“BDV”).
  • BVDV bovine viral diarrhea virus
  • CSFV classical swine fever virus
  • BDV border disease virus
  • compositions and methods useful for treating liver disorders such as HCV infection in a subject are provided herein. Further provided are dosage forms useful for such methods.
  • alkyl refers to a saturated straight or branched hydrocarbon.
  • the alkyl group is a primary, secondary, or tertiary hydrocarbon.
  • the alkyl group includes one to ten carbon atoms, i.e., C ⁇ to C 10 alkyl.
  • the alkyl group is selected from the group consisting of methyl, CF 3 , CC1 3 , CFC1 2 , CF 2 C1, ethyl, CH 2 CF 3 , CF 2 CF 3 , propyl, isopropyl, butyl, isobutyl, secbutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, 3- methylpentyl, 2,2-dimethylbutyl, and 2,3-dimethylbutyl.
  • the term includes both substituted and unsubstituted alkyl groups, including halogenated alkyl groups.
  • the alkyl group is a fluorinated alkyl group.
  • moieties with which the alkyl group can be substituted are selected from the group consisting of halogen (fluoro, chloro, bromo or iodo), hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in Greene, et ah, Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991, hereby incorporated by reference.
  • lower alkyl refers to a saturated straight or branched hydrocarbon having one to six carbon atoms, i.e., C ⁇ to C 6 alkyl.
  • the lower alkyl group is a primary, secondary, or tertiary hydrocarbon. The term includes both substituted and unsubstituted moieties.
  • cycloalkyl refers to a saturated cyclic hydrocarbon.
  • the cycloalkyl group may be a saturated, and/or bridged, and/or non-bridged, and/or a fused bicyclic group.
  • the cycloalkyl group includes three to ten carbon atoms, i.e., C 3 to C 10 cycloalkyl.
  • the cycloalkyl has from 3 to 15 (C 3-15 ), from 3 to 10 (C 3-10 ), or from 3 to 7 (C 3 _ 7 ) carbon atoms.
  • the cycloalkyl group is
  • bicyclo[2.1.1]hexyl bicyclo[2.2.1]heptyl, decalinyl, or adamantyl.
  • cycloalkenyl refers to an unsaturated cyclic hydrocarbon.
  • cycloalkenyl refers to mono- or multicyclic ring systems that include at least one double bond.
  • the cycloalkenyl group may be a bridged, non-bridged, and/or a fused bicyclic group.
  • the cycloalkyl group includes three to ten carbon atoms, i.e., C 3 to C 10 cycloalkyl.
  • the cycloalkenyl has from 3 to 7 (C 3-10 ), or from 4 to 7 (C 3 _ 7 ) carbon atoms.
  • Alkylene refers to divalent saturated aliphatic hydrocarbon groups particularly having from one to eleven carbon atoms which can be straight-chained or branched. In certain embodiments, the alkylene group contains 1 to 10 carbon atoms. The term includes both substituted and unsubstituted moieties. This term is exemplified by groups such as methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), the propylene isomers (e.g., -CH 2 CH 2 CH 2 - and - CH(CH 3 )CH 2 -) and the like.
  • alkenyl refers to monovalent olefmically unsaturated hydrocarbon groups, in certain embodiment, having up to about 11 carbon atoms, from 2 to 8 carbon atoms, or from 2 to 6 carbon atoms, which can be straight-chained or branched and having at least 1 or from 1 to 2 sites of olefinic unsaturation. The term includes both substituted and unsubstituted moieties.
  • Alkynyl refers to acetylenically unsaturated hydrocarbon groups, in certain embodiments, having up to about 11 carbon atoms or from 2 to 6 carbon atoms which can be straight-chained or branched and having at least 1 or from 1 to 2 sites of alkynyl unsaturation.
  • alkynyl groups include acetylenic, ethynyl (-C ⁇ CH), propargyl (-CH 2 C ⁇ CH), and the like.
  • aryl refers to phenyl, biphenyl, or naphthyl.
  • the term includes both substituted and unsubstituted moieties.
  • An aryl group can be substituted with any described moiety, including, but not limited to, one or more moieties selected from the group consisting of halogen (fluoro, chloro, bromo or iodo), alkyl, haloalkyl, hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in Greene, et al.
  • Alkoxy or "alkoxyl” as used herein refers to the group -OR' where R' is alkyl or cycloalkyl. Alkoxy groups include, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1 ,2-dimethylbutoxy, and the like.
  • Alkoxycarbonyl refers to a radical -C(0)-alkoxy where alkoxy is as defined herein.
  • Amino refers to the radical -NH 2 .
  • Carboxyl or “carboxy” refers to the radical -C(0)OH.
  • Carboxylene refers to the radical -C(0)0-.
  • aminocarboxylene refers to the radical -C(0)ONH 2 or -OC(0)NH 2 . In certain embodiments, the term “aminocarboxylene” refers to the radical -C(0)ONH 2 . In certain embodiments, the term “aminocarboxylene” refers to the radical -OC(0)NH 2 .
  • alkylamino or “arylamino” refers to an amino group that has one or two alkyl or aryl substituents, respectively.
  • the alkyl substituent is lower alkyl.
  • the alkyl or lower alkyl is unsubstituted.
  • Halogen or "halo” refers to chloro, bromo, fluoro or iodo.
  • “Monoalkylamino” refers to the group alkyl-NR '-, wherein R' is selected from hydrogen and alkyl or cycloalkyl.
  • Thioalkoxy refers to the group -SR' where R' is alkyl or cycloalkyl.
  • heterocyclyl refers to a monovalent monocyclic non- aromatic ring system and/or multicyclic ring system that contains at least one non-aromatic ring, wherein one or more of the non-aromatic ring atoms are heteroatoms independently selected from O, S, or N; and the remaining ring atoms are carbon atoms.
  • the heterocyclyl or heterocyclic group has from 3 to 20, from 3 to 15, from 3 to 10, from 3 to 8, from 4 to 7, or from 5 to 6 ring atoms.
  • Heterocyclyl groups are bonded to the rest of the molecule through the non-aromatic ring.
  • the heterocyclyl is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include a fused or bridged ring system, and in which the nitrogen or sulfur atoms may be optionally oxidized, the nitrogen atoms may be optionally quaternized, and some rings may be partially or fully saturated, or aromatic.
  • the heterocyclyl may be attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable compound. Examples of such heterocyclic radicals include, but are not limited to, azepinyl, benzodioxanyl,
  • benzodioxolyl benzofuranonyl, benzopyranonyl, benzopyranyl, benzotetrahydrofuranyl, benzotetrahydrothienyl, benzothiopyranyl, benzoxazinyl, ⁇ -carbolinyl, chromanyl, chromonyl, cinnolinyl, coumarinyl, decahydroisoquinolinyl, dihydrobenzisothiazinyl,
  • heterocyclic may also be optionally substituted as described herein.
  • heteroaryl refers to refers to a monovalent monocyclic aromatic group and/or multicyclic aromatic group that contain at least one aromatic ring, wherein at least one aromatic ring contains one or more heteroatoms independently selected from O, S, and N in the ring. Heteroaryl groups are bonded to the rest of the molecule through the aromatic ring.
  • Each ring of a heteroaryl group can contain one or two O atoms, one or two S atoms, and/or one to four N atoms, provided that the total number of heteroatoms in each ring is four or less and each ring contains at least one carbon atom.
  • the heteroaryl has from 5 to 20, from 5 to 15, or from 5 to 10 ring atoms.
  • monocyclic heteroaryl groups include, but are not limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, and triazolyl.
  • bicyclic heteroaryl groups include, but are not limited to, benzofuranyl, benzimidazolyl,
  • benzotriazolyl benzoxazolyl, furopyridyl, imidazopyridinyl, imidazothiazolyl, indolizinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridyl,
  • heteroaryl examples include, but are not limited to, acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, perimidinyl, phenanthrolinyl, phenanthridinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and xanthenyl.
  • heteroaryl may also be optionally substituted as described herein.
  • alkylaryl refers to an aryl group with an alkyl substituent.
  • aralkyl or “arylalkyl” includes an alkyl group with an aryl substituent.
  • alkylheterocyclyl refers to a heterocyclyl group with an alkyl substituent.
  • alkylheterocyclyl includes an alkyl group with a heterocyclyl
  • alkylheteroaryl refers to a heteroaryl group with an alkyl substituent.
  • alkylheteroaryl includes an alkyl group with a heteroaryl substituent.
  • protecting group refers to a group that is added to an oxygen, nitrogen, or phosphorus atom to prevent its further reaction or for other purposes.
  • oxygen and nitrogen protecting groups are known to those skilled in the art of organic synthesis.
  • “Pharmaceutically acceptable salt” refers to any salt of a compound provided herein which retains its biological properties and which is not toxic or otherwise undesirable for pharmaceutical use. Such salts may be derived from a variety of organic and inorganic counter-ions well known in the art. Such salts include, but are not limited to: (1) acid addition salts formed with organic or inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, sulfamic, acetic, trifluoroacetic, trichloroacetic, propionic, hexanoic,
  • cyclopentylpropionic glycolic, glutaric, pyruvic, lactic, malonic, succinic, sorbic, ascorbic, malic, maleic, fumaric, tartaric, citric, benzoic, 3-(4-hydroxybenzoyl)benzoic, picric, cinnamic, mandelic, phthalic, lauric, methanesulfonic, ethanesulfonic, 1 ,2-ethane-disulfonic, 2- hydroxyethanesulfonic, benzenesulfonic, 4-chlorobenzenesulfonic, 2-naphthalenesulfonic, 4- toluenesulfonic, camphoric, camphorsulfonic, 4-methylbicyclo[2.2.2]-oct-2-ene-l-carboxylic, glucoheptonic, 3-phenylpropionic, trimethylacetic, tert-butylacetic, lauryl sulfuric, glu
  • Pharmaceutically acceptable salts further include, by way of example only and without limitation, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium and the like, and when the compound contains a basic functionality, salts of non-toxic organic or inorganic acids, such as hydrohalides, e.g.
  • benzenesulfonate (besylate), 4-chlorobenzenesulfonate, 2-naphthalenesulfonate, 4- toluenesulfonate, camphorate, camphorsulfonate, 4-methylbicyclo[2.2.2]-oct-2-ene-l- carboxylate, glucoheptonate, 3-phenylpropionate, trimethylacetate, tert-butyl acetate, lauryl sulfate, gluconate, benzoate, glutamate, hydroxynaphthoate, salicylate, stearate,
  • purine or "pyrimidine” base refers to, but is not limited to, adenine, N 6 - alkylpurines, N 6 -acylpurines (wherein acyl is C(0)(alkyl, aryl, alkylaryl, or arylalkyl), N 6 - benzylpurine, N 6 -halopurine, N 6 -vinylpurine, N 6 -acetylenic purine, N 6 -acyl purine,
  • Purine bases include, but are not limited to, guanine, adenine, hypoxanthine, 7-deazaguanine, 7-deazaadenine, 2,6- diaminopurine, and 6-chloropurine.
  • Functional oxygen and nitrogen groups on the base can be protected as necessary or desired.
  • Suitable protecting groups are well known to those skilled in the art, and include trimethylsilyl, dimethylhexylsilyl, t-butyldimethylsilyl, and t- butyldiphenylsilyl, trityl, alkyl groups, and acyl groups such as acetyl and propionyl, methanesulfonyl, and p-toluenesulfonyl.
  • acyl or "0-linked ester” refers to a group of the formula C(0)R', wherein R' is alkyl or cycloalkyl (including lower alkyl), carboxylate reside of amino acid, aryl including phenyl, alkaryl, arylalkyl including benzyl, alkoxyalkyl including methoxymethyl, aryloxyalkyl such as phenoxymethyl; or substituted alkyl (including lower alkyl), aryl including phenyl optionally substituted with chloro, bromo, fluoro, iodo, Ci to C 4 alkyl or Ci to C 4 alkoxy, sulfonate esters such as alkyl or arylalkyl sulphonyl including methanesulfonyl, the mono, di or triphosphate ester, trityl or monomethoxy-trityl, substituted benzyl, alkaryl, arylalkyl including benz
  • Aryl groups in the esters optimally comprise a phenyl group.
  • acyl groups include acetyl, trifluoroacetyl, methylacetyl, cyclpropylacetyl, propionyl, butyryl, hexanoyl, heptanoyl, octanoyl, neo-heptanoyl, phenylacetyl, 2-acetoxy-2-phenylacetyl, diphenylacetyl, ⁇ -methoxy-a-trifluoromethyl-phenylacetyl, bromoacetyl, 2-nitro- benzeneacetyl, 4-chloro-benzeneacetyl, 2-chloro-2,2-diphenylacetyl, 2-chloro-2 -phenylacetyl, trimethylacetyl, chlorodifluoroacetyl, perfluoroacetyl, fluoroacetyl, bromodi
  • amino acid refers to naturally occurring and synthetic ⁇ , ⁇ ⁇ or ⁇ amino acids, and includes but is not limited to, amino acids found in proteins, i.e. glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan, proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartate, glutamate, lysine, arginine and histidine.
  • the amino acid is in the L-configuration.
  • the amino acid can be a derivative of alanyl, valinyl, leucinyl, isoleuccinyl, prolinyl, phenylalaninyl, tryptophanyl, methioninyl, glycinyl, serinyl, threoninyl, cysteinyl, tyrosinyl, asparaginyl, glutaminyl, aspartoyl, glutaroyl, lysinyl, argininyl, histidinyl, ⁇ -alanyl, ⁇ -valinyl, ⁇ -leucinyl, ⁇ - isoleuccinyl, ⁇ -prolinyl, ⁇ -phenylalaninyl, ⁇ -tryptophanyl, ⁇ -methioninyl, ⁇ -glycinyl, ⁇ - serinyl, ⁇ -threoninyl, ⁇ -cystein
  • amino acid derivative refers to a group derivable from a naturally or non-naturally occurring amino acid, as described and exemplified herein.
  • Amino acid derivatives are apparent to those of skill in the art and include, but are not limited to, ester, amino alcohol, amino aldehyde, amino lactone, and N-methyl derivatives of naturally and non- naturally occurring amino acids.
  • an amino acid derivative is provided as a substituent of a compound described herein, wherein the substituent is -NH-G(Sc)-C(0)-Q or -OC(0)G(Sc)-Q, wherein Q is -SR, -NRR or alkoxyl, R is hydrogen or alkyl, Sc is a side chain of a naturally occurring or non-naturally occurring amino acid and G is C 1 -C 2 alkyl.
  • G is Ci alkyl and Sc is selected from the group consisting of hydrogen, alkyl, heteroalkyl, arylalkyl and heteroarylalkyl.
  • nucleoside composition that includes at least 85 or 90% by weight, in certain embodiments 95%, 98 % , 99% or 100% by weight, of the designated enantiomer of that nucleoside.
  • the compounds are substantially free of enantiomers.
  • nucleoside composition refers to a nucleoside composition that includes at least 85, 90%, 95%, 98%, 99% to 100% by weight, of the nucleoside, the remainder comprising other chemical species or enantiomers.
  • solvent refers to a compound provided herein or a salt thereof, that further includes a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. Where the solvent is water, the solvate is a hydrate.
  • Isotopic composition refers to the amount of each isotope present for a given atom
  • naturally occurring isotopic composition refers to the naturally occurring isotopic composition or abundance for a given atom
  • Atoms containing their natural isotopic composition may also be referred to herein as "non-enriched" atoms.
  • the atoms of the compounds recited herein are meant to represent any stable isotope of that atom. For example, unless otherwise stated, when a position is designated specifically as “H” or “hydrogen”, the position is understood to have hydrogen at its natural isotopic composition.
  • Isotopic enrichment refers to the percentage of incorporation of an amount of a specific isotope at a given atom in a molecule in the place of that atom's natural isotopic abundance. For example, deuterium enrichment of 1% at a given position means that 1% of the molecules in a given sample contain deuterium at the specified position. Because the naturally occurring distribution of deuterium is about 0.0156%, deuterium enrichment at any position in a compound synthesized using non-enriched starting materials is about 0.0156%.
  • the isotopic enrichment of the compounds provided herein can be determined using conventional analytical methods known to one of ordinary skill in the art, including mass spectrometry and nuclear magnetic resonance spectroscopy.
  • “Isotopically enriched” refers to an atom having an isotopic composition other than the natural isotopic composition of that atom. “Isotopically enriched” may also refer to a compound containing at least one atom having an isotopic composition other than the natural isotopic composition of that atom.
  • alkyl As used herein, “alkyl,” “cycloalkyl,” “alkenyl,” “cycloalkenyl,” “alkynyl,” “aryl,” “alkoxy,” “alkoxycarbonyl,” “amino,” “carboxyl,” “alkylamino,” “arylamino,” “thioalkyoxy,” “heterocyclyl,” “heteroaryl,” “alkylheterocyclyl,” “alkylheteroaryl,” “acyl,” “aralkyl,”
  • alkaryl optionally comprise deuterium at one or more positions where hydrogen atoms are present, and wherein the deuterium composition of the atom or atoms is other than the natural isotopic composition.
  • alkyl cycloalkyl
  • alkenyl cycloalkenyl
  • alkynyl aryl
  • alkoxy alkoxycarbonyl
  • thioalkyoxy thioalkyoxy
  • alkaryl, purine,” “pyrimidine,” “carboxyl” and “amino acid” groups optionally comprise carbon- 13 at an amount other than the natural isotopic composition.
  • EC 5 o refers to a dosage, concentration or amount of a particular test compound that elicits a dose-dependent response at 50% of maximal expression of a particular response that is induced, provoked or potentiated by the particular test compound.
  • the IC 5 o refers to an amount, concentration or dosage of a particular test compound that achieves a 50% inhibition of a maximal response in an assay that measures such response.
  • the term "host”, as used herein, refers to any unicellular or multicellular organism in which the virus can replicate, including cell lines and animals, and in certain embodiments, a human. Alternatively, the host can be carrying a part of the Flaviviridae viral genome, whose replication or function can be altered by the compounds of the present invention.
  • the term host specifically includes infected cells, cells transfected with all or part of the Flaviviridae genome and animals, in particular, primates (including chimpanzees) and humans. In most animal applications of the present invention, the host is a human patient. Veterinary applications, in certain indications, however, are clearly anticipated by the present invention (such as chimpanzees).
  • the terms “subject” and “patient” are used interchangeably herein.
  • the terms “subject” and “subjects” refer to an animal, such as a mammal including a non- primate ⁇ e.g., a cow, pig, horse, cat, dog, rat, and mouse) and a primate ⁇ e.g., a monkey such as a cynomolgous monkey, a chimpanzee and a human), and for example, a human.
  • the subject is refractory or non-responsive to current treatments for hepatitis C infection.
  • the subject is a farm animal ⁇ e.g., a horse, a cow, a pig, etc.) or a pet ⁇ e.g., a dog or a cat). In certain embodiments, the subject is a human.
  • a therapeutic agent refers to any agent(s) which can be used in the treatment or prevention of a disorder or one or more symptoms thereof.
  • the term “therapeutic agent” includes a compound provided herein.
  • a therapeutic agent is an agent which is known to be useful for, or has been or is currently being used for the treatment or prevention of a disorder or one or more symptoms thereof.
  • “Therapeutically effective amount” refers to an amount of a compound or composition that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease.
  • a “therapeutically effective amount” can vary depending on, inter alia, the compound, the disease and its severity, and the age, weight, etc., of the subject to be treated.
  • Treating" or “treatment” of any disease or disorder refers, in certain embodiments, to ameliorating a disease or disorder that exists in a subject.
  • “treating” or “treatment” includes ameliorating at least one physical parameter, which may be indiscernible by the subject.
  • “treating” or “treatment” includes modulating the disease or disorder, either physically (e.g., stabilization of a discernible symptom) or physiologically (e.g., stabilization of a physical parameter) or both.
  • “treating” or “treatment” includes delaying the onset of the disease or disorder.
  • prophylactic agent and “prophylactic agents” as used refer to any agent(s) which can be used in the prevention of a disorder or one or more symptoms thereof.
  • the term “prophylactic agent” includes a compound provided herein.
  • the term “prophylactic agent” does not refer a compound provided herein.
  • a prophylactic agent is an agent which is known to be useful for, or has been or is currently being used to prevent or impede the onset, development, progression and/or severity of a disorder.
  • prophylactically effective amount refers to the amount of a therapy (e.g. , prophylactic agent) which is sufficient to result in the prevention or reduction of the development, recurrence or onset of one or more symptoms associated with a disorder, or to enhance or improve the prophylactic effect(s) of another therapy (e.g., another prophylactic agent).
  • a therapy e.g. , prophylactic agent
  • another therapy e.g., another prophylactic agent
  • 3 ',5 '-cyclic phosphate prodrug compounds useful for the treatment of Flaviviridae infections such as HCV infection.
  • the 3 ',5 '-cyclic phosphate prodrug compounds can be formed as described herein and used for the treatment of
  • Flaviviridae infections such as HCV infection.
  • each h E is independently alkyl, substituted alkyl, aryl, or heteroaryl
  • each Ar is independently an arylene or heteroarylene
  • each L is independently alkylene or substituted alkylene
  • each R is independently hydrogen, alkyl, substituted alkyl, aryl, or heteroaryl
  • each R A is independently a carbocyclic or heterocyclic ring
  • each p is independently 0 or 1. All combinations of such embodiments are within the scope of this disclosure.
  • VHIb (Villa) (VHIb); or pharmaceutically acceptable salts, solvates, stereoisomeric forms, tautomeric forms or polymorphic forms thereof, wherein each of Y and Z are as described in the context of Formula (VIII).
  • each X is independently alkoxyl, hydrogen, or hydroxyl and Y and Z are as described in the context of Formula (VIII).
  • each Y is independently hydroxyl or fluoro. In certain embodiments, each Y is hydroxyl. In certain embodiments, each Y is fluoro.
  • ring A is oxacyclopropyl or oxacyclobutyl.
  • a compound of Formula Va or Vb is provided:
  • Va (Vb) or pharmaceutically acceptable salts, solvates, stereoisomer ⁇ forms, tautomeric forms or polymorphic forms thereof, wherein ring A, X, Y, and Z are as defined in the context of Formula VI; or X, Y, and Z are as defined in the context of Formula VIII.
  • each D is indep
  • each E is independently alkyl, substituted alkyl, aryl, or heteroaryl
  • each Ar is independently an arylene or heteroarylene
  • each L is independently alkylene, or substituted alkylene
  • each R is independently hydrogen, alkyl, substituted alkyl, aryl, or heteroaryl
  • each R A is independently a carbocyclic or heterocyclic ring
  • each p is independently 0 or 1
  • each of R and R is independently hydrogen, Ci-Cio alkyl, Ci-Cio substituted alkyl, C5-C 10 aryl, or C5-C 10 heteroaryl
  • R and R are each independently selected from hydrogen, an optionally substituted Ci_ 6 alkyl, an optionally substituted C 2 _ 6 alkenyl, an optionally substituted C 2 _ 6
  • each R B and R C 1 is independently hydrogen or methyl.
  • each R B and R is hydrogen.
  • each R B and R c is methyl.
  • each R B is hydrogen and each R is methyl.
  • each W is independently hydrogen.
  • each W is independently fluoro.
  • each W is
  • each Z is independently -LSC(0)LC(0)0(L) P CR 3 or - LSC(0)LNRC(0)0(L) P CR 3 ; each L is independently alkylene or substituted alkylene; each R is independently hydrogen, alkyl, substituted alkyl, aryl, or heteroaryl; and each p is independently 0 or 1.
  • each Z is independently -LSC(0)LC(0)0(L) P CR 3 ; where L, R, and p are as defined in the context of Formula (IX). In certain embodiments, each Z is independently -LSC(0)LNRC(0)0(L) P CR 3 ; where L, R, and p are as defined in the context of Formula (IX).
  • each Base is X is as defined in the
  • each Base is independently selected from:
  • each X is independently Ci-Cio alkoxyl, hydrogen, or hydroxyl. In certain embodiments, each X is independently C1-C5 alkoxyl. In certain embodiments, each X is independently Ci-C 2 alkoxyl. In certain embodiments, each X is methoxyl. In certain embodiments, each X is ethoxyl.
  • each L is independently Ci-Cio alkylene or Ci-Cio substituted alkylene. In certain embodiments, each L is independently C 1 -C 5 alkylene or C substituted alkylene. In certain embodiments, each L is independently C 1 -C 10 alkylene. In certain embodiments, each L is independently C 1 -C 10 substituted alkylene.
  • each Z is independently -(CR 2 ) m C(0)0(CR 2 ) n CR 3 , -
  • each Z is independently - (CR 2 ) m C(0)0(CR 2 ) n CR 3 .
  • each Z is independently - (CR 2 ) m ArC(0)0(CR 2 ) n CR 3 .
  • each Z is independently - CR(E)(CR 2 ) n OC(0)0(CR 2 ) n CR 3 .
  • each Z is independently - (CR 2 ) m SC(0)(CR 2 ) m OH.
  • each Z is independently - (CR 2 ) m SC(0)(CR 2 ) m OC(0)(CR 2 ) n CR 3 . In certain embodiments, each Z is independently - (CR 2 ) m S-S(CR 2 ) n CR 3 . In certain embodiments, each Z is independently -(CR 2 ) m S- S(CR 2 ) m OH. In certain embodiments, each Z is independently -(CR 2 ) m NRC(0)0(CR 2 ) n CR 3 .
  • each Z is independently . In certain embodiments, each Z is independently -(CR 2 ) n B. In certain embodiments, each Z is independently - (CR 2 ) m NRC(0)D. In certain embodiments, each Z is independently - (CR 2 ) m NRC(0)CH(OH)(CR 2 ) 2 OH. In certain embodiments, each Z is independently -
  • each E is independently C 1 -C 10 alkyl, C 1 -C 10 substituted alkyl, C5-C 10 aryl, or C5-C 10 heteroaryl. In certain embodiments, each E is independently Ci- C 10 alkyl. In certain embodiments, each E is independently C 1 -C 10 substituted alkyl. In certain embodiments, each E is independently C 5 -C 10 aryl. In certain embodiments, each E is independently C 5 -C 10 heteroaryl. [0091] In certain embodiments, each Ar is independently C5-C10 arylene or C5-C10
  • each Ar is independently C5-C10 arylene. In certain embodiments, each Ar is independently C5-C10 heteroarylene.
  • each R is independently hydrogen, C1-C10 alkyl, C1-C10 substituted alkyl, C5-C10 aryl, or C5-C10 heteroaryl. In certain embodiments, each R is independently hydrogen, C1-C5 alkyl, C1-C5 substituted alkyl, C5-C10 aryl, or C5-C10 heteroaryl. In certain embodiments, each R is independently hydrogen, fluoro, C1-C10 alkyl, C1-C10 substituted alkyl, C5-C10 aryl, or C5-C10 heteroaryl.
  • each R A is independently a 3-20 membered carbocyclic or heterocyclic ring. In certain embodiments, each R A is independently a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl group. In certain embodiments, each R A is
  • each R A is independently an aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, or azepinyl group. In certain embodiments, each R A is independently a thiiranyl, thietanyl, thiofanyl, thianyl, or thiepanyl group.
  • each Y is independently fluoro, acetoxyl, or hydroxyl and
  • each Base is ertain embodiments, each Y is independently fluoro, acetoxyl, or
  • Base is ; and each Z is -(CR 2 ) m C(0)0(CR 2 ) n CR 3 ; wherein R is as defined herein in the context of Formula VIII; each m is independently an integer selected over the range of 1 to 10; and each n is independently an integer selected over the range of 0 to 10.
  • each Y is independently fluoro, acetoxyl, or hydroxyl
  • each Z is -(CR 2 ) m ArC(0)0(CR 2 ) n CR 3 ; wherein R and Ar are as defined herein in the context of Formula VIII; each m is independently an integer selected over the range of 1 to 10; and each n is independently an integer selected over the range of 0 to 10.
  • each Y is independently fluoro, acetoxyl, or hydroxyl;
  • Base is ; and each Z is -CR(E)(CR 2 ) n OC(0)0(CR 2 ) n CR 3 ; wherein R and E are as defined herein in the context of Formula VIII; and each n is independently an integer selected over the range of 0 to 10.
  • each Y is independently fluoro, acetoxyl, or hydroxyl
  • each Z is -(CR 2 ) m SC(0)(CR 2 ) m OH; wherein R is as defined herein in the context of Formula VIII; and each m is independently an integer selected over the range of 1 to 10.
  • each Y is independently fluoro, acetoxyl, or hydroxyl; Base is NH 2
  • each Z is -(CR 2 ) m SC(0)(CR 2 ) m OC(0)(CR 2 ) n CR3; wherein R is as defined herein in the context of Formula VIII; each m is independently an integer selected over the range of 1 to 10; and each n is independently an integer selected over the range of 0 to 10.
  • each Y is independently fluoro, acetoxyl, or hydroxyl
  • Base is ; and each Z is -(CR 2 ) m S-S(CR 2 ) n CR 3 ; wherein R is as defined herein in the context of Formula VIII; each m is independently an integer selected over the range of 1 to 10; and each n is independently an integer selected over the range of 0 to 10.
  • each Y is independently fluoro, acetoxyl, or hydroxyl
  • each Z is -(CR 2 ) m S-S(CR 2 ) m OH wherein R is as defined herein in the context of Formula VIII; and each m is independently an integer selected over the range of 1 to 10.
  • each Y is independently fluoro, acetoxyl, or hydroxyl; Base is
  • each Z is -(CR 2 ) m RC(0)0(CR 2 ) n CR 3 ; wherein R is as defined herein in the context of Formula VIII; each m is independently an integer selected over the range of 1 to 10; and each n is independently an integer selected over the range of 0 to 10.
  • each Y is independently fluoro, acetoxyl, or hydroxyl
  • Base is ; and each Z is , wherein B is as defined in the context of
  • each Y is independently fluoro, acetoxyl, or hydroxyl
  • Base is ; and each Z is -(CR 2 ) n B, wherein R and B are as defined in the context of
  • each Y is independently fluoro, acetoxyl, or hydroxyl
  • each Z is -(CR 2 ) m NRC(0)D; wherein R and D are as defined herein in the context of Formula VIII; and each m is independently an integer selected over the range of 1 to 10.
  • each Y is independently fluoro, acetoxyl, or hydroxyl; Base is NH 2
  • each Z is -(CR 2 ) m NRC(0)CH(OH)(CR 2 ) 2 OH; wherein R is as defined herein in the context of Formula VIII; and each m is independently an integer selected over the range of 1 to 10.
  • each Y is independently fluoro, acetoxyl, or hydroxyl; Base is
  • each Z is -(CR 2 ) n CR(R A )C(0)0(CR 2 ) n CR 3 ; wherein R is as defined herein in the context of Formula VIII; and each n is independently an integer selected over the range of O to 10.
  • Y is fluoro. In certain embodiments, Y is acetoxyl. In certain embodiments, Y is hydroxyl. In certain embodiments, Y is fluoro and each Base is
  • Y is fluoro; each Base is ; and each Z is -
  • Y is fluoro; each Base is ; and each Z is -
  • each Base is ; and each Z is -CR(E)(CR 2 ) n OC(0)0(CR 2 ) n CR 3 ; wherein R and
  • n is independently an integer selected over the range of 0 to 10.
  • Y is fluoro; each Base is ; and each Z is -
  • Y is fluoro; each Base is ; and each Z is -(CR 2 ) m SC(0)(CR 2 ) m OC(0)(CR 2 ) n CR 3 ; wherein R is as defined herein in the context of Formula VIII; each m is independently an integer selected over the range of 1 to 10; and each n is independently an integer selected over the range of 0 to 10.
  • Y is fluoro; each Base is ; and each Z is -
  • Y is fluoro; each Base is ; and each Z is -
  • each Base is ; and each Z is -(CR 2 ) m RC(0)0(CR 2 ) n CR 3 ; wherein R is as defined herein in the context of Formula VIII; each m is independently an integer selected over the range of 1 to 10; and each n is independently an integer selected over the range of 0 to 10.
  • Y is fluoro; each Base is ; and each Z is -(CR 2 ) n B, wherein R and B are as defined in the context of Formula VIII; and each n is independently an integer selected over the range of 0 to 10.
  • Y is fluoro; each Base is ; and each Z is -
  • Y is fluoro; each Base is ; and each Z is -(CR 2 ) m NRC(0)CH(OH)(CR 2 ) 2 0H; wherein
  • R is as defined herein in the context of Formula VIII; and each m is independently an integer
  • Y is fluoro; each Base is ; and each Z is -(CR 2 ) friendshipCR(R A )C(0)0(CR 2 ) felicitCR 3 ; wherein R is as defined herein in the context of Formula VIII; and each n is independently an integer selected over the range of 0 to 10.
  • Y is acetoxyl and each Base is .
  • Y is acetoxyl; each Base is ; and each Z is -(CR 2 ) m C(0)0(CR 2 ) n CR 3 ; wherein R is as defined herein in the context of Formula VIII; each m is independently an integer selected over the range of 1 to 10; and each n is independently an integer selected over the range of 0 to 10.
  • Y is acetoxyl; each Base is ; and each Z is -
  • each Base is ; and each Z is -CR(E)(CR 2 ) n OC(0)0(CR 2 ) n CR 3 ; wherein R and E are as defined herein in the context of Formula VIII; and each n is independently an integer selected over the range of 0 to 10.
  • Y is acetoxyl; each Base is ; and each Z is -
  • Y is acetoxyl; each Base is ; and each Z is -(CR2) m SC(0)(CR2) m OC(0)(CR2)nCR 3 ; wherein R is as defined herein in the context of Formula VIII; each m is independently an integer selected over the range of 1 to 10; and each n is independently an integer selected over the range of 0 to 10.
  • Y is acetoxyl; each Base is ; and each Z is -
  • Y is acetoxyl; each Base is ; and each Z is -
  • each Base is ; and each Z is -(CR 2 ) m NRC(0)0(CR 2 ) n CR3; wherein R is as defined herein in the context of Formula VIII; each m is independently an integer selected over the range of 1 to 10; and each n is independently an integer selected over the range of 0 to 10.
  • Y is acetoxyl; each Base is ; and each Z is , wherein B is as defined in the context of Formula VIII.
  • Y is acetoxyl; each Base is ; and each Z is -(CR 2 ) n B, wherein R and B are as defined in the context of Formula VIII; and each n is independently an integer selected over the range of 0 to 10.
  • Y is acetoxyl; each Base is ; and each Z is -
  • Y is acetoxyl; each Base is ; and each Z is -(CR 2 ) m NRC(0)CH(OH)(CR 2 ) 2 OH; wherein R is as defined herein in the context of Formula VIII; and each m is independently an integer selected over the range of 1 to 10.
  • Y is acetoxyl; each Base is
  • each Z is -(CR 2 ) n CR(R A )C(0)0(CR 2 ) n CR 3 ; wherein R is as defined herein in the context of Formula VIII; and each n is independently an integer selected over the range of O to 10.
  • Y is hydroxyl and each Base is .
  • Y is hydroxyl; each Base is ; and each Z is -(CR 2 ) m C(0)0(CR 2 ) n CR 3 ; wherein R is as defined herein in the context of Formula VIII; each m is independently an integer selected over the range of 1 to 10; and each n is independently an integer selected over the range of 0 to 10.
  • Y is hydroxyl; each Base is ; and each Z is -
  • each Base is ; and each Z is -CR(E)(CR 2 ) n OC(0)0(CR 2 ) n CR 3 ; wherein R and E are as defined herein in the context of Formula VIII; and each n is independently an integer selected over the range of 0 to 10.
  • Y is hydroxyl; each Base is ; and each Z is -
  • Y is hydroxyl; each Base is ; and each Z is -(CR 2 ) m SC(0)(CR 2 ) m OC(0)(CR 2 ) n CR 3 ; wherein R is as defined herein in the context of Formula VIII; each m is independently an integer selected over the range of 1 to 10; and each n is independently an integer selected over the range of 0 to 10.
  • Y is hydroxyl; each Base is ; and each Z is -
  • Y is hydroxyl; each Base is ; and each Z is -
  • each Base is ; and each Z is -(CR 2 ) m RC(0)0(CR 2 ) n CR 3 ; wherein R is as defined herein in the context of Formula VIII; each m is independently an integer selected over the range of 1 to 10; and each n is independently an integer selected over the range of 0 to 10.
  • Y is hydroxyl; each Base is ; and each Z is , wherein B is as defined in the context of Formula VIII.
  • Y is hydroxyl; each Base is ; and each Z is -(CR 2 ) n B, wherein R and B are as defined in the context of Formula VIII; and each n is independently an integer selected over the range of 0 to 10.
  • Y is hydroxyl; each Base is ; and each Z is -
  • Y is hydroxyl; each Base is ; and each Z is -(CR 2 ) m NRC(0)CH(OH)(CR 2 ) 2 OH; wherein R is as defined herein in the context of Formula VIII; and each m is independently an integer selected over the range of 1 to 10.
  • Y is hydroxyl; each Base is ; and each Z is -(CR 2 ) m NRC(0)CH(OH)(CR 2 ) 2 OH; wherein R is as defined herein in the context of Formula VIII; and each m is independently an integer selected over the range of 1 to 10.
  • Y is hydroxyl; each Base is
  • each Z is -(CR 2 ) n CR(R A )C(0)0(CR 2 ) n CR 3 ; wherein R is as defined herein in the context of Formula VIII; and each n is independently an integer selected over the range of O to 10.
  • Base is and X is Ci-Cio alkoxyl.
  • Base is and X is h drox l. In certain embodiments
  • Base is and X is hydrogen. In certain embodiments, Base is
  • Base is and X is ethoxyl
  • Base is , each Y is independently fluoro, acetoxyl, or hydroxyl and X is hydrogen. In certain embodiments, each Y is independently fluoro, acetoxyl, or hydroxyl; X is hydrogen; and each Z is -(CR 2 ) m C(0)0(CR 2 ) n CR 3 ; wherein R is as defined herein in the context of Formula VIII; each m is independently an integer selected over the range of 1 to 10; and each n is independently an integer selected over the range of 0 to 10.
  • Base is , each Y is independently fluoro, acetoxyl, or hydroxyl; X is hydrogen; and each Z is -(CR 2 ) m rC(0)0(CR 2 ) n CR3; wherein R and Ar are as defined herein in the context of Formula VIII; each m is independently an integer selected over the range of 1 to 10; and each n is independently an integer selected over the range of 0 to 10.
  • each Y is independently fluoro, acetoxyl, or hydroxyl
  • X is hydrogen
  • each Z is -CR(E)(CR 2 ) n OC(0)0(CR 2 ) n CR 3 ; wherein R and E are as defined herein in the context of Formula VIII; and each n is independently an integer selected over the range of 0 to 10.
  • Base is , each Y is independently fluoro, acetoxyl, or hydroxyl; X is hydrogen; and each Z is -(CR 2 ) m SC(0)(CR 2 ) m OH; wherein R is as defined herein in the context of Formula VIII; and each m is independently an integer selected over the range of 1 to 10.
  • each Y is independently fluoro, acetoxyl, or hydroxyl
  • X is hydrogen
  • each Z is -(CR2) m SC(0)(CR2) m OC(0)(CR 2 )nCR3; wherein R is as defined herein in the context of Formula VIII; each m is independently an integer selected over the range of 1 to 10; and each n is independently an integer selected over the range of 0 to
  • Base is , each Y is independently fluoro, acetoxyl, or hydroxyl; X is hydrogen; and each Z is -(CR 2 ) m S-S(CR 2 ) n CR3; wherein R is as defined herein in the context of Formula VIII; each m is independently an integer selected over the range of 1 to 10; and each n is independently an integer selected over the range of 0 to 10.
  • Base is , each Y is independently fluoro, acetoxyl, or hydroxyl; X is hydrogen; and each Z is -(CR 2 ) m S-S(CR 2 ) m OH wherein R is as defined herein in the context of Formula VIII; and each m is independently an integer selected over the range of 1 to 10.
  • each Y is independently fluoro, acetoxyl, or hydroxyl
  • X is hydrogen
  • each Z is -(CR 2 ) m RC(0)0(CR 2 ) n CR 3 ; wherein R is as defined herein in the context of Formula VIII; each m is independently an integer selected over the range of 1 to 10; and each n is independently an integer selected over the range of 0 to 10.
  • Base is Y is independently fluoro, acetoxyl, or hydroxyl; X is hydrogen; and ea ch Z is , wherein B is as defined in the context of Formula VIII.
  • each Y is independently fluoro, acetoxyl, or hydroxyl
  • X is hydrogen
  • each Z is -(CR 2 ) n B, wherein R and B are as defined in the context of Formula VIII; and each n is independently an integer selected over the range of 0 to 10.
  • Base is , each Y is independently fluoro, acetoxyl, or hydroxyl; X is hydrogen; and each Z is -(CR 2 ) m NRC(0)D; wherein R and D are as defined herein in the context of Formula VIII; and each m is independently an integer selected over the range of 1 to 10.
  • each Y is independently fluoro, acetoxyl, or hydroxyl; X is hydrogen; and each Z is -(CR 2 ) m NRC(0)CH(OH)(CR 2 ) 2 0H;
  • each Y is independently fluoro, acetoxyl, or hydroxyl
  • X is hydrogen
  • each Z is -(CR 2 )nCR(R A )C(0)0(CR 2 )nCR3; wherein R is as defined herein in the context of Formula VIII; and each n is independently an integer selected over the range of 0 to 10.
  • Base is , each Y is independently fluoro, acetoxyl, or hydroxyl and X is hydroxyl.
  • each Y is independently fluoro, acetoxyl, or hydroxyl;
  • X is hydroxyl; and
  • each Z is -(CR 2 ) m C(0)0(CR 2 ) n CR 3 ; wherein R is as defined herein in the context of Formula VIII;
  • each m is independently an integer selected over the range of 1 to 10; and each n is independently an integer selected over the range of 0 to 10.
  • Base is , each Y is independently fluoro, acetoxyl, or hydroxyl; X is hydroxyl; and each Z is -(CR 2 ) m rC(0)0(CR 2 ) n CR 3 ; wherein R and Ar are as defined herein in the context of Formula VIII; each m is independently an integer selected over the range of 1 to 10; and each n is independently an integer selected over the range of 0 to 10.
  • each Y is independently fluoro, acetoxyl, or hydroxyl;
  • X is hydroxyl; and
  • each Z is -CR(E)(CR2)nOC(0)0(CR 2 )nCR 3 ; wherein R and E are as defined herein in the context of Formula VIII; and each n is independently an integer selected over the range of 0 to 10.
  • Base is , each Y is independently fluoro, acetoxyl, or hydroxyl; X is hydroxyl; and each Z is -(CR 2 ) m SC(0)(CR 2 ) m OH; wherein R is as defined herein in the context of Formula VIII; and each m is independently an integer selected over the range of 1 to 10.
  • each Y is independently fluoro, acetoxyl, or hydroxyl;
  • X is hydroxyl; and
  • each Z is -(CR2) m SC(0)(CR2) m OC(0)(CR 2 )nCR3; wherein R is as defined herein in the context of Formula VIII;
  • Base is , each Y is independently fluoro, acetoxyl, or hydroxyl; X is hydroxyl; and each Z is -(CR 2 ) m S-S(CR 2 ) n CR 3 ; wherein R is as defined herein in the context of Formula VIII; each m is independently an integer selected over the range of 1 to 10; and each n is independently an integer selected over the range of 0 to 10.
  • Base is , each Y is independently fluoro, acetoxyl, or hydroxyl; X is hydroxyl; and each Z is -(CR 2 ) m S-S(CR 2 ) m OH wherein R is as defined herein in the context of Formula VIII; and each m is independently an integer selected over the range of 1 to 10.
  • each Y is independently fluoro, acetoxyl, or hydroxyl;
  • X is hydroxyl; and
  • each Z is -(CR 2 ) m NRC(0)0(CR 2 ) n CR3; wherein R is as defined herein in the context of Formula VIII;
  • Base is Y is independently fluoro, acetoxyl, or hydroxyl; X is hydroxyl; and eac h Z is , wherein B is as defined in the context of Formula VIII.
  • each Y is independently fluoro, acetoxyl, or hydroxyl; X is hydroxyl; and each Z is -(CR2) n B, wherein R and B are as defined in the context of Formula VIII; and each n is independently an integer selected over the range of 0 to 10.
  • Base is , each Y is independently fluoro, acetoxyl, or hydroxyl; X is hydroxyl; and each Z is -(CR2) m NRC(0)D; wherein R and D are as defined herein in the context of Formula VIII; and each m is independently an integer selected over the range of 1 to 10.
  • each Y is independently fluoro, acetoxyl, or hydroxyl; X is hydroxyl; and each Z is -(CR 2 ) m NRC(0)CH(OH)(CR 2 )20H; wherein R is as defined herein in the context of Formula VIII; and each m is independently an integer selected over the range of 1 to 10.
  • each Y is independently fluoro, acetoxyl, or hydroxyl;
  • X is hydroxyl; and
  • each Z is -(CR2)nCR(R A )C(0)0(CR 2 )nCR 3 ; wherein R is as defined herein in the context of Formula VIII; and each n is independently an integer selected over the range of 0 to 10.
  • Base is , each Y is independently fluoro, acetoxyl, or hydroxyl and X is methoxyl.
  • each Y is independently fluoro, acetoxyl, or hydroxyl;
  • X is methoxyl; and
  • each Z is -(CR 2 ) m C(0)0(CR 2 ) n CR 3 ; wherein R is as defined herein in the context of Formula VIII; each m is independently an integer selected over the range of 1 to 10; and each n is independently an integer selected over the range of 0 to 10.
  • Base is , each Y is independently fluoro, acetoxyl, or hydroxyl; X is methoxyl; and each Z is -(CR 2 ) m rC(0)0(CR 2 ) n CR3; wherein R and Ar are as defined herein in the context of Formula VIII; each m is independently an integer selected over the range of 1 to 10; and each n is independently an integer selected over the range of 0 to 10.
  • each Y is independently fluoro, acetoxyl, or hydroxyl;
  • X is methoxyl; and
  • each Z is -CR(E)(CR2)nOC(0)0(CR 2 )nCR 3 ; wherein R and E are as defined herein in the context of Formula VIII; and each n is independently an integer selected over the range of 0 to 10.
  • Base is , each Y is independently fluoro, acetoxyl, or hydroxyl; X is methoxyl; and each Z is -(CR 2 ) m SC(0)(CR 2 ) m OH; wherein R is as defined herein in the context of Formula VIII; and each m is independently an integer selected over the range of 1 to 10.
  • each Y is independently fluoro, acetoxyl, or hydroxyl;
  • X is methoxyl; and
  • each Z is -(CR 2 ) m SC(0)(CR 2 ) m OC(0)(CR 2 ) n CR3; wherein R is as defined herein in the context of Formula VIII; each m is independently an integer selected over the range of 1 to 10; and each n is independently an integer selected over the range of 0 to 10.
  • Base is , each Y is independently fluoro, acetoxyl, or hydroxyl; X is methoxyl; and each Z is -(CR 2 ) m S-S(CR 2 ) n CR3; wherein R is as defined herein in the context of Formula VIII; each m is independently an integer selected over the range of 1 to 10; and each n is independently an integer selected over the range of 0 to 10.
  • Base is , each Y is independently fluoro, acetoxyl, or hydroxyl; X is methoxyl; and each Z is -(CR 2 ) m S-S(CR 2 ) m OH wherein R is as defined herein in the context of Formula VIII; and each m is independently an integer selected over the range of 1 to 10.
  • each Y is independently fluoro, acetoxyl, or hydroxyl;
  • X is methoxyl; and
  • each Z is -(CR 2 ) m NRC(0)0(CR 2 ) n CR3; wherein R is as defined herein in the context of Formula VIII;
  • Base is Y is independently fluoro, acetoxyl, or hydroxyl; X is methoxyl; and ea ch Z is , wherein B is as defined in the context of Formula VIII.
  • each Y is independently fluoro, acetoxyl, or hydroxyl; X is methoxyl; and each Z is -(CR 2 ) n B, wherein R and B are as defined in the context of Formula VIII; and each n is independently an integer selected over the range of 0 to 10.
  • Base is , each Y is independently fluoro, acetoxyl, or hydroxyl; X is methoxyl; and each Z is -(CR 2 ) m NRC(0)D; wherein R and D are as defined herein in the context of Formula VIII; and each m is independently an integer selected over the range of 1 to 10.
  • each Y is independently fluoro, acetoxyl, or hydroxyl; X is methoxyl; and each Z is -(CR 2 ) m NRC(0)CH(OH)(CR 2 ) 2 OH; wherein R is as defined herein in the context of Formula VIII; and each m is independently an integer selected over the range of 1 to 10.
  • each Y is independently fluoro, acetoxyl, or hydroxyl;
  • X is methoxyl; and
  • each Z is -(CR 2 ) n CR(R A )C(0)0(CR 2 ) n CR 3 ; wherein R is as defined herein in the context of Formula VIII; and each n is independently an integer selected over the range of 0 to 10.
  • Base is , each Y is independently fluoro, acetoxyl, or hydroxyl and X is ethoxyl.
  • each Y is independently fluoro, acetoxyl, or hydroxyl;
  • X is ethoxyl; and
  • each Z is -(CR 2 ) m C(0)0(CR 2 ) n CR 3 ; wherein R is as defined herein in the context of Formula VIII; each m is independently an integer selected over the range of 1 to 10; and each n is independently an integer selected over the range of 0 to 10.
  • Base is , each Y is independently fluoro, acetoxyl, or hydroxyl; X is ethoxyl; and each Z is -(CR 2 ) m ArC(0)0(CR 2 ) n CR 3 ; wherein R and Ar are as defined herein in the context of Formula VIII; each m is independently an integer selected over the range of 1 to 10; and each n is independently an integer selected over the range of 0 to 10.
  • each Y is independently fluoro, acetoxyl, or hydroxyl;
  • X is ethoxyl; and
  • each Z is -CR(E)(CR 2 ) n OC(0)0(CR 2 ) n CR 3 ; wherein R and E are as defined herein in the context of Formula VIII; and each n is independently an integer selected over the range of 0 to 10.
  • Base is , each Y is independently fluoro, acetoxyl, or hydroxyl; X is ethoxyl; and each Z is -(CR 2 ) m SC(0)(CR 2 ) m OH; wherein R is as defined herein in the context of Formula VIII; and each m is independently an integer selected over the range of 1 to 10.
  • each Y is independently fluoro, acetoxyl, or hydroxyl;
  • X is ethoxyl; and
  • each Z is -(CR 2 ) m SC(0)(CR 2 ) m OC(0)(CR 2 ) n CR3; wherein R is as defined herein in the context of Formula VIII; each m is independently an integer selected over the range of 1 to 10; and each n is independently an integer selected over the range of 0 to 10.
  • Base is , each Y is independently fluoro, acetoxyl, or hydroxyl; X is ethoxyl; and each Z is -(CR 2 ) m S-S(CR 2 ) n CR3; wherein R is as defined herein in the context of Formula VIII; each m is independently an integer selected over the range of 1 to 10; and each n is independently an integer selected over the range of 0 to 10.
  • Base is , each Y is independently fluoro, acetoxyl, or hydroxyl; X is ethoxyl; and each Z is -(CR 2 ) m S-S(CR 2 ) m OH wherein R is as defined herein in the context of Formula VIII; and each m is independently an integer selected over the range of 1 to 10.
  • each Y is independently fluoro, acetoxyl, or hydroxyl;
  • X is ethoxyl; and
  • each Z is -(CR 2 ) m NRC(0)0(CR 2 ) n CR3; wherein R is as defined herein in the context of Formula VIII;
  • Base is h Y is independently fluoro, acetoxyl, or hydroxyl; X is ethoxyl; and each Z is , wherein B is as defined in the context of Formula VIII.
  • each Y is independently fluoro, acetoxyl, or hydroxyl; X is ethoxyl; and each Z is -(CR 2 ) n B, wherein R and B are as defined in the context of Formula VIII; and each n is independently an integer selected over the range of 0 to 10.
  • Base is , each Y is independently fluoro, acetoxyl, or hydroxyl; X is ethoxyl; and each Z is -(CR 2 ) m NRC(0)D; wherein R and D are as defined herein in the context of Formula VIII; and each m is independently an integer selected over the range of 1 to 10.
  • each Y is independently fluoro, acetoxyl, or hydroxyl; X is ethoxyl; and each Z is -(CR 2 ) m NRC(0)CH(OH)(CR 2 ) 2 0H; wherein R is as defined herein in the context of Formula VIII; and each m is independently an integer selected over the range of 1 to 10.
  • each Y is independently fluoro, acetoxyl, or hydroxyl;
  • X is ethoxyl; and
  • each Z is -(CR 2 ) n CR(R A )C(0)0(CR 2 ) n CR 3 ; wherein R is as defined herein in the context of Formula VIII; and each n is independently an integer selected over the range of 0 to 10.
  • Base is , Y is fluoro. In certain embodiments, Y is acetoxyl. In certain embodiments, Y is hydroxyl. In certain embodiments, Y is fluoro and each X is independently hydrogen, hydroxyl, methoxy or ethoxy. In certain embodiments, Y is fluoro; each X is independently hydrogen, hydroxyl, methoxy or ethoxy; and each Z is -(CR 2 ) m C(0)0(CR 2 ) n CR 3 ; wherein R is as defined herein in the context of Formula VIII; each m is independently an integer selected over the range of 1 to 10; and each n is independently an integer selected over the range of 0 to 10.
  • Base is , Y is fluoro; each X is independently hydrogen, hydroxyl, methoxy or ethoxy; and each Z is -
  • each m is independently an integer selected over the range of 1 to 10; and each n is independently an integer selected over the range of 0 to 10.
  • Y is fluoro; each X is independently hydrogen, hydroxyl, methoxy or ethoxy; and each Z is - CR(E)(CR 2 ) n OC(0)0(CR 2 ) n CR 3 ; wherein R and E are as defined herein in the context of Formula VIII; and each n is independently an integer selected over the range of 0 to 10.
  • Base is , Y is fluoro; each X is independently hydrogen, hydroxyl, methoxy or ethoxy; and each Z is - (CR 2 ) m SC(0)(CR 2 ) m OH; wherein R is as defined herein in the context of Formula VIII; and each m is independently an integer selected over the range of 1 to 10.
  • Base is , Y is fluoro; each X is independently hydrogen, hydroxyl, methoxy or ethoxy; and each Z is -(CR 2 ) m S-S(CR 2 ) n CR 3 ; wherein R is as defined herein in the context of Formula VIII; each m is independently an integer selected over the range of 1 to 10; and each n is independently an integer selected over the range of 0 to 10.
  • Base is , Y is fluoro; each X is independently hydrogen, hydroxyl, methoxy or ethoxy; and each Z is -(CR 2 ) m S-S(CR 2 ) m OH wherein R is as defined herein in the context of Formula VIII; and each m is independently an integer selected over the range of 1 to 10.
  • Base is , Y is fluoro; each X is independently hydrogen, hydroxyl, methoxy or ethoxy; and each Z , wherein B is as defined in the context of Formula VIII.
  • Y is fluoro; each X is independently hydrogen, hydroxyl, methoxy or ethoxy; and each Z is -(CR 2 ) n B, wherein R and B are as defined in the context of Formula VIII; and each n is independently an integer selected over the range of 0 to 10.
  • Base is , Y is fluoro; each X is independently hydrogen, hydroxyl, methoxy or ethoxy; and each Z is -(CR 2 ) m NRC(0)D; wherein R and D are as defined herein in the context of Formula VIII; and each m is independently an integer selected over the range of 1 to 10.
  • Y is fluoro; each X is independently hydrogen, hydroxyl, methoxy or ethoxy; and each Z is - (CR 2 ) m NRC(0)CH(OH)(CR 2 ) 2 OH; wherein R is as defined herein in the context of Formula VIII; and each m is independently an integer selected over the range of 1 to 10.
  • Base is , Y is acetoxyl and each X is independently hydrogen, hydroxyl, methoxy or ethoxy.
  • Base is , Y is acetoxyl; each X is independently hydrogen, hydroxyl, methoxy or ethoxy; and each Z is -
  • each m is independently an integer selected over the range of 1 to 10; and each n is independently an integer selected over the range of 0 to 10.
  • Y is acetoxyl; each X is independently hydrogen, hydroxyl, methoxy or ethoxy; and each Z is - CR(E)(CR 2 ) n OC(0)0(CR 2 ) n CR 3 ; wherein R and E are as defined herein in the context of Formula VIII; and each n is independently an integer selected over the range of 0 to 10.
  • Base is , Y is acetoxyl; each X is independently hydrogen, hydroxyl, methoxy or ethoxy; and each Z is - (CR 2 ) m SC(0)(CR 2 ) m OH; wherein R is as defined herein in the context of Formula VIII; and each m is independently an integer selected over the range of 1 to 10.
  • Base is , Y is acetoxyl; each X is independently hydrogen, hydroxyl, methoxy or ethoxy; and each Z is -(CR 2 ) m S-S(CR 2 ) n CR 3 ; wherein R is as defined herein in the context of Formula VIII; each m is independently an integer selected over the range of 1 to 10; and each n is independently an integer selected over the range of 0 to 10.
  • Base is , Y is acetoxyl; each X is independently hydrogen, hydroxyl, methoxy or ethoxy; and each Z is -(CR 2 ) m S-S(CR 2 ) m OH wherein R is as defined herein in the context of Formula VIII; and each m is independently an integer selected over the range of 1 to 10.
  • Base is , Y is acet xyl; each X is independently hydrogen, hydroxyl, methoxy or ethoxy; and each Z is , wherein B is as defined in the context of Formula VIII.
  • Y is acetoxyl; each X is independently hydrogen, hydroxyl, methoxy or ethoxy; and each Z is -(CR 2 ) n B, wherein R and B are as defined in the context of Formula VIII; and each n is independently an integer selected over the range of 0 to 10.
  • Base is , Y is acetoxyl; each X is independently hydrogen, hydroxyl, methoxy or ethoxy; and each Z is -(CR 2 ) m NRC(0)D; wherein R and D are as defined herein in the context of Formula VIII; and each m is independently an integer selected over the range of 1 to 10.
  • Y is acetoxyl; each X is independently hydrogen, hydroxyl, methoxy or ethoxy; and each Z is - (CR 2 ) m NRC(0)CH(OH)(CR 2 ) 2 0H; wherein R is as defined herein in the context of Formula VIII; and each m is independently an integer selected over the range of 1 to 10.
  • Base is , Y is hydroxyl and each X is independently hydrogen, hydroxyl, methoxy or ethoxy.
  • Base is , Y is hydroxyl; each X is independently hydrogen, hydroxyl, methoxy or ethoxy; and each Z is -
  • each m is independently an integer selected over the range of 1 to 10; and each n is independently an integer selected over the range of 0 to 10.
  • Base is , Y is hydroxyl; each X is independently hydrogen, hydroxyl, methoxy or ethoxy; and each Z is - (CR 2 ) m SC(0)(CR 2 ) m OH; wherein R is as defined herein in the context of Formula VIII; and each m is independently an integer selected over the range of 1 to 10.
  • Base is , Y is hydroxyl; each X is independently hydrogen, hydroxyl, methoxy or ethoxy; and each Z is -(CR 2 ) m S-S(CR 2 ) n CR3; wherein R is as defined herein in the context of Formula VIII; each m is independently an integer selected over the range of 1 to 10; and each n is independently an integer selected over the range of 0 to 10.
  • Base is , Y is hydroxyl; each X is independently hydrogen, hydroxyl, methoxy or ethoxy; and each Z is -(CR 2 ) m S-S(CR 2 ) m OH wherein R is as defined herein in the context of Formula VIII; and each m is independently an integer selected over the range of 1 to 10.
  • Base is , Y is hydroxyl; each X is independently hydrogen, hydroxyl, methoxy or ethoxy; and each Z , wherein B is as defined in the context of Formula VIII.
  • Y is hydroxyl; each X is independently hydrogen, hydroxyl, methoxy or ethoxy; and each Z is -(CR 2 ) n B, wherein R and B are as defined in the context of Formula VIII; and each n is independently an integer selected over the range of 0 to 10.
  • Base is , Y is hydroxyl; each X is independently hydrogen, hydroxyl, methoxy or ethoxy; and each Z is -(CR 2 ) m NRC(0)D; wherein R and D are as defined herein in the context of Formula VIII; and each m is independently an integer selected over the range of 1 to 10.
  • Y is hydroxyl; each X is independently hydrogen, hydroxyl, methoxy or ethoxy; and each Z is - (CR 2 ) m NRC(0)CH(OH)(CR 2 ) 2 0H; wherein R is as defined herein in the context of Formula VIII; and each m is independently an integer selected over the range of 1 to 10.
  • the four optical isomers therefore are represented by the following configurations (when orienting the sugar moiety in a horizontal plane such that the oxygen atom is in the back): cis (with both groups “up”, which corresponds to the configuration of naturally occurring ⁇ -D nucleosides), cis (with both groups “down”, which is a non-naturally occurring ⁇ -L configuration), trans (with the C2' substituent "up” and the C4' substituent "down”), and trans (with the C2' substituent "down” and the C4' substituent "up”).
  • the "D-nucleosides” are cis nucleosides in a natural
  • optically active materials examples include at least the following. i) physical separation of crystals - a technique whereby macroscopic
  • crystals of the individual enantiomers are manually separated. This technique can be used if crystals of the separate enantiomers exist, i.e., the material is a conglomerate, and the crystals are visually distinct; ii) simultaneous crystallization - a technique whereby the individual
  • enantiomers are separately crystallized from a solution of the racemate, possible only if the latter is a conglomerate in the solid state; iii) enzymatic resolutions - a technique whereby partial or complete
  • enzymatic asymmetric synthesis - a synthetic technique whereby at least one step of the synthesis uses an enzymatic reaction to obtain an enantiomerically pure or enriched synthetic precursor of the desired enantiomer
  • chemical asymmetric synthesis - a synthetic technique whereby the desired enantiomer is synthesized from an achiral precursor under conditions that produce asymmetry (i.e., chirality) in the product, which may be achieved using chiral catalysts or chiral auxiliaries
  • the resulting diastereomers are then separated by chromatography or crystallization by virtue of their now more distinct structural differences and the chiral auxiliary later removed to obtain the desired enantiomer; first- and second-order asymmetric transformations - a technique whereby diastereomers from the racemate equilibrate to yield a preponderance in solution of the diastereomer from the desired enantiomer or where preferential crystallization of the diastereomer from the desired enantiomer perturbs the equilibrium such that eventually in principle all the material is converted to the crystalline diastereomer from the desired enantiomer.
  • kinetic resolutions - this technique refers to the achievement of partial or complete resolution of a racemate (or of a further resolution of a partially resolved compound) by virtue of unequal reaction rates of the enantiomers with a chiral, non-racemic reagent or catalyst under kinetic conditions; enantiospecific synthesis from non-racemic precursors - a synthetic technique whereby the desired enantiomer is obtained from non-chiral starting materials and where the stereochemical integrity is not or is only minimally compromised over the course of the synthesis; chiral liquid chromatography - a technique whereby the enantiomers of a racemate are separated in a liquid mobile phase by virtue of their differing interactions with a stationary phase.
  • the stationary phase can be made of chiral material or the mobile phase can contain an additional chiral material to provoke the differing interactions; xi) chiral gas chromatography - a technique whereby the racemate is
  • volatilized and enantiomers are separated by virtue of their differing interactions in the gaseous mobile phase with a column containing a fixed non-racemic chiral adsorbent phase; xii) extraction with chiral solvents - a technique whereby the enantiomers are separated by virtue of preferential dissolution of one enantiomer into a particular chiral solvent; xiii) transport across chiral membranes - a technique whereby a racemate is placed in contact with a thin membrane barrier.
  • the barrier typically separates two miscible fluids, one containing the racemate, and a driving force such as concentration or pressure differential causes preferential transport across the membrane barrier. Separation occurs as a result of the non-racemic chiral nature of the membrane which allows only one enantiomer of the racemate to pass through.
  • compositions of 3 ',5 '-cyclic phosphate prodrug compounds that are substantially free of a designated enantiomer of that compound.
  • the compounds are
  • the composition includes that includes a compound that is at least 85, 90%, 95%, 98%, 99% to 100% by weight, of the compound, the remainder comprising other chemical species or enantiomers.
  • isotopically enriched compounds including but not limited to isotopically enriched 3 ',5 '-cyclic phosphate prodrug compounds.
  • Isotopic enrichment of a drug can be used, for example, to (1) reduce or eliminate unwanted metabolites, (2) increase the half-life of the parent drug, (3) decrease the number of doses needed to achieve a desired effect, (4) decrease the amount of a dose necessary to achieve a desired effect, (5) increase the formation of active metabolites, if any are formed, and/or (6) decrees the production of deleterious metabolites in specific tissues and/or create a more effective drug and/or a safer drug for combination therapy, whether the combination therapy is intentional or not.
  • KIE Kinetic Isotope Effect
  • DKIE Deuterium Kinetic Isotope Effect
  • the magnitude of the DKIE can be expressed as the ratio between the rates of a given reaction in which a C-H bond is broken, and the same reaction where deuterium is substituted for hydrogen.
  • the DKIE can range from about 1 (no isotope effect) to very large numbers, such as 50 or more, meaning that the reaction can be fifty, or more, times slower when deuterium is substituted for hydrogen.
  • High DKIE values may be due in part to a phenomenon known as tunneling, which is a consequence of the uncertainty principle.
  • Tunneling is ascribed to the small mass of a hydrogen atom, and occurs because transition states involving a proton can sometimes form in the absence of the required activation energy. Because deuterium has more mass than hydrogen, it statistically has a much lower probability of undergoing this phenomenon.
  • substitution of tritium ("T") for hydrogen results in yet a stronger bond than deuterium and gives numerically larger isotope effects.
  • substitution of isotopes for other elements including, but not limited to, 13 C or 14 C for carbon, 33 S, 34 S, or 36 S for sulfur, 15 N for nitrogen, and 17 0 or 18 0 for oxygen, may lead to a similar kinetic isotope effect.
  • the DKIE was used to decrease the hepatotoxicity of halothane by presumably limiting the production of reactive species such as trifluoroacetyl chloride.
  • the animal body expresses a variety of enzymes for the purpose of eliminating foreign substances, such as therapeutic agents, from its circulation system.
  • enzymes include the cytochrome P450 enzymes ("CYPs"), esterases, proteases, reductases, dehydrogenases, and monoamine oxidases, to react with and convert these foreign substances to more polar intermediates or metabolites for renal excretion.
  • CYPs cytochrome P450 enzymes
  • esterases enzymes
  • proteases e.g., reductases, dehydrogenases, and monoamine oxidases
  • Some of the most common metabolic reactions of pharmaceutical compounds involve the oxidation of a carbon-hydrogen (C-H) bond to either a carbon-oxygen (C-O) or carbon-carbon (C-C) pi-bond.
  • C-H carbon-hydrogen
  • C-O carbon-oxygen
  • C-C carbon-carbon
  • the resultant metabolites may be stable or unstable under physiological conditions, and can have
  • isotopic enrichment at certain positions of a compound provided herein will produce a detectable KIE that will affect the pharmacokinetic, pharmacologic, and/or toxicological profiles of a compound provided herein in comparison with a similar compound having a natural isotopic composition.
  • one or more protection or deprotection steps may be included in the methods of preparation described in Scheme 1.
  • 3 ',5 '-cyclic phosphate prodrug compounds can be formulated into pharmaceutical compositions using methods available in the art and those disclosed herein. Any of the compounds disclosed herein can be provided in the appropriate pharmaceutical composition and be administered by a suitable route of administration.
  • compositions containing at least one compound as described herein including a compound of Formula I-IXe or l-67b, if appropriate in the salt form, either used alone or in the form of a combination with one or more compatible and pharmaceutically acceptable carriers, such as diluents or adjuvants, or with another anti-HCV agent.
  • the second agent can be formulated or packaged with the compound provided herein.
  • the second agent will only be formulated with the compound provided herein when, according to the judgment of those of skill in the art, such co-formulation should not interfere with the activity of either agent or the method of administration.
  • the compound provided herein and the second agent are formulated separately. They can be packaged together, or packaged separately, for the convenience of the practitioner of skill in the art.
  • the active agents provided herein may be administered by any conventional route, in particular orally, parenterally, rectally or by inhalation (e.g. in the form of aerosols).
  • the compound provided herein is administered orally.
  • Use may be made, as solid compositions for oral administration, of tablets, pills, hard gelatin capsules, powders or granules.
  • the active product is mixed with one or more inert diluents or adjuvants, such as sucrose, lactose or starch.
  • compositions can comprise substances other than diluents, for example a lubricant, such as magnesium stearate, or a coating intended for controlled release.
  • a lubricant such as magnesium stearate
  • compositions for oral administration of solutions which are pharmaceutically acceptable, suspensions, emulsions, syrups and elixirs containing inert diluents, such as water or liquid paraffin.
  • solutions which are pharmaceutically acceptable, suspensions, emulsions, syrups and elixirs containing inert diluents, such as water or liquid paraffin.
  • inert diluents such as water or liquid paraffin.
  • These compositions can also comprise substances other than diluents, for example wetting, sweetening or flavoring products.
  • compositions for parenteral administration can be emulsions or sterile solutions. Use may be made, as solvent or vehicle, of propylene glycol, a polyethylene glycol, vegetable oils, in particular olive oil, or injectable organic esters, for example ethyl oleate. These compositions can also contain adjuvants, in particular wetting, isotonizing, emulsifying, dispersing and stabilizing agents. Sterilization can be carried out in several ways, for example using a bacteriological filter, by radiation or by heating. They can also be prepared in the form of sterile solid compositions which can be dissolved at the time of use in sterile water or any other injectable sterile medium.
  • compositions for rectal administration are suppositories or rectal capsules which contain, in addition to the active principle, excipients such as cocoa butter, semisynthetic glycerides or polyethylene glycols.
  • the compositions can also be aerosols.
  • the compositions can be stable sterile solutions or solid compositions dissolved at the time of use in apyrogenic sterile water, in saline or any other pharmaceutically acceptable vehicle.
  • the active principle is finely divided and combined with a water-soluble solid diluent or vehicle, for example dextran, mannitol or lactose.
  • compositions provided herein is a pharmaceutical composition or a single unit dosage form.
  • Pharmaceutical compositions and single unit dosage forms provided herein comprise a prophylactically or therapeutically effective amount of one or more prophylactic or therapeutic agents (e.g. , a compound provided herein, or other prophylactic or therapeutic agent), and a typically one or more pharmaceutically acceptable carriers or excipients.
  • prophylactic or therapeutic agents e.g. , a compound provided herein, or other prophylactic or therapeutic agent
  • “pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.
  • carrier includes a diluent, adjuvant (e.g., Freund's adjuvant (complete and incomplete)), excipient, or vehicle with which the therapeutic is administered.
  • Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water can be used as a carrier when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Examples of suitable pharmaceutical carriers are described in
  • Typical pharmaceutical compositions and dosage forms comprise one or more excipients.
  • Suitable excipients are well-known to those skilled in the art of pharmacy, and non-limiting examples of suitable excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.
  • Lactose free compositions can comprise excipients that are well known in the art and are listed, for example, in the U.S. Pharmocopia (USP) SP (XXI)/NF (XVI). In general, lactose free compositions comprise an active ingredient, a binder/filler, and a lubricant in pharmaceutically compatible and pharmaceutically acceptable amounts.
  • Exemplary lactose free dosage forms comprise an active ingredient, microcrystalline cellulose, pre gelatinized starch, and magnesium stearate.
  • anhydrous pharmaceutical compositions and dosage forms comprising active ingredients, since water can facilitate the degradation of some compounds.
  • water e.g., 5%
  • water is widely accepted in the pharmaceutical arts as a means of simulating long term storage in order to determine characteristics such as shelf life or the stability of formulations over time. See, e.g., Jens T. Carstensen, Drug Stability: Principles & Practice, 2d. Ed., Marcel Dekker, NY, NY, 1995, pp. 379 80.
  • water and heat accelerate the decomposition of some compounds.
  • the effect of water on a formulation can be of great significance since moisture and/or humidity are commonly encountered during manufacture, handling, packaging, storage, shipment, and use of formulations.
  • Anhydrous pharmaceutical compositions and dosage forms provided herein can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions.
  • Pharmaceutical compositions and dosage forms that comprise lactose and at least one active ingredient that comprises a primary or secondary amine can be anhydrous if substantial contact with moisture and/or humidity during manufacturing, packaging, and/or storage is expected.
  • An anhydrous pharmaceutical composition should be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions can be packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs.
  • compositions and dosage forms that comprise one or more compounds that reduce the rate by which an active ingredient will decompose.
  • Such compounds which are referred to herein as “stabilizers,” include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers.
  • antioxidants such as ascorbic acid, pH buffers, or salt buffers.
  • the pharmaceutical compositions and single unit dosage forms can take the form of solutions, suspensions, emulsion, tablets, pills, capsules, powders, sustained-release
  • Oral formulation can include standard carriers such as
  • compositions and dosage forms will contain a prophylactically or therapeutically effective amount of a prophylactic or therapeutic agent, in certain embodiments, in purified form, together with a suitable amount of carrier so as to provide the form for proper administration to the subject.
  • the formulation should suit the mode of administration.
  • the pharmaceutical compositions or single unit dosage forms are sterile and in suitable form for administration to a subject, for example, an animal subject, such as a mammalian subject, for example, a human subject.
  • a pharmaceutical composition is formulated to be compatible with its intended route of administration.
  • routes of administration include, but are not limited to, parenteral, e.g., intravenous, intradermal, subcutaneous, intramuscular, subcutaneous, oral, buccal, sublingual, inhalation, intranasal, transdermal, topical, transmucosal, intra-tumoral, intra-synovial and rectal administration.
  • the composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous, subcutaneous, intramuscular, oral, intranasal or topical administration to human beings.
  • a pharmaceutical composition is formulated in accordance with routine procedures for subcutaneous administration to human beings.
  • compositions for intravenous administration are solutions in sterile isotonic aqueous buffer.
  • the composition may also include a solubilizing agent and a local anesthetic such as lignocamne to ease pain at the site of the injection.
  • dosage forms include, but are not limited to: tablets; caplets; capsules, such as soft elastic gelatin capsules; cachets; troches; lozenges; dispersions; suppositories; ointments; cataplasms (poultices); pastes; powders; dressings; creams; plasters; solutions; patches; aerosols ⁇ e.g., nasal sprays or inhalers); gels; liquid dosage forms suitable for oral or mucosal administration to a subject, including suspensions ⁇ e.g., aqueous or non-aqueous liquid suspensions, oil in water emulsions, or a water in oil liquid emulsions), solutions, and elixirs; liquid dosage forms suitable for parenteral administration to a subject; and sterile solids ⁇ e.g.
  • compositions, shape, and type of dosage forms provided herein will typically vary depending on their use.
  • a dosage form used in the initial treatment of viral infection may contain larger amounts of one or more of the active ingredients it comprises than a dosage form used in the maintenance treatment of the same infection.
  • a parenteral dosage form may contain smaller amounts of one or more of the active ingredients it comprises than an oral dosage form used to treat the same disease or disorder.
  • compositions are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampoule or sachette indicating the quantity of active agent.
  • a hermetically sealed container such as an ampoule or sachette indicating the quantity of active agent.
  • the composition is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline.
  • an ampoule of sterile water for injection or saline can be provided so that the ingredients may be mixed prior to administration.
  • Typical dosage forms comprise a compound provided herein, or a pharmaceutically acceptable salt, solvate or hydrate thereof lie within the range of from about 0.1 mg to about 1000 mg per day, given as a single once-a-day dose in the morning or as divided doses throughout the day taken with food.
  • Particular dosage forms can have about 0.1 , 0.2, 0.3, 0.4, 0.5, 1.0, 2.0, 2.5, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 100, 200, 250, 500 or 1000 mg of the active compound.
  • compositions that are suitable for oral administration can be presented as discrete dosage forms, such as, but are not limited to, tablets ⁇ e.g., chewable tablets), caplets, capsules, and liquids ⁇ e.g., flavored syrups).
  • dosage forms contain predetermined amounts of active ingredients, and may be prepared by methods of pharmacy well known to those skilled in the art. See generally, Remington's Pharmaceutical Sciences, 20th ed., Mack Publishing, Easton PA (2000).
  • the oral dosage forms are solid and prepared under anhydrous conditions with anhydrous ingredients, as described in detail herein.
  • anhydrous ingredients as described in detail herein.
  • the scope of the compositions provided herein extends beyond anhydrous, solid oral dosage forms. As such, further forms are described herein.
  • Typical oral dosage forms are prepared by combining the active ingredient(s) in an intimate admixture with at least one excipient according to conventional pharmaceutical compounding techniques.
  • Excipients can take a wide variety of forms depending on the form of preparation desired for administration.
  • excipients suitable for use in oral liquid or aerosol dosage forms include, but are not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents.
  • excipients suitable for use in solid oral dosage forms include, but are not limited to, starches, sugars, micro crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents.
  • tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid excipients are employed. If desired, tablets can be coated by standard aqueous or non-aqueous techniques. Such dosage forms can be prepared by any of the methods of pharmacy. In general, pharmaceutical compositions and dosage forms are prepared by uniformly and intimately admixing the active ingredients with liquid carriers, finely divided solid carriers, or both, and then shaping the product into the desired presentation if necessary.
  • a tablet can be prepared by compression or molding.
  • Compressed tablets can be prepared by compressing in a suitable machine the active ingredients in a free flowing form such as powder or granules, optionally mixed with an excipient.
  • Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • excipients that can be used in oral dosage forms include, but are not limited to, binders, fillers, disintegrants, and lubricants. Binders suitable for use in
  • compositions and dosage forms include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pre gelatinized starch, hydroxypropyl methyl cellulose, (e.g., Nos. 2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof.
  • natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl
  • fillers suitable for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre gelatinized starch, and mixtures thereof.
  • the binder or filler in pharmaceutical compositions is typically present in from about 50 to about 99 weight percent of the pharmaceutical composition or dosage form.
  • Suitable forms of microcrystalline cellulose include, but are not limited to, the materials sold as AVICEL PH 101 , AVICEL PH 103 AVICEL RC 581 , AVICEL PH 105 (available from FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, PA), and mixtures thereof.
  • a specific binder is a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose sold as AVICEL RC 581.
  • Suitable anhydrous or low moisture excipients or additives include AVICEL PH 103TM and Starch 1500 LM.
  • Disintegrants are used in the compositions to provide tablets that disintegrate when exposed to an aqueous environment. Tablets that contain too much disintegrant may disintegrate in storage, while those that contain too little may not disintegrate at a desired rate or under the desired conditions. Thus, a sufficient amount of disintegrant that is neither too much nor too little to detrimentally alter the release of the active ingredients should be used to form solid oral dosage forms. The amount of disintegrant used varies based upon the type of formulation, and is readily discernible to those of ordinary skill in the art. Typical
  • compositions comprise from about 0.5 to about 15 weight percent of disintegrant, specifically from about 1 to about 5 weight percent of disintegrant.
  • Disintegrants that can be used in pharmaceutical compositions and dosage forms include, but are not limited to, agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, pre gelatinized starch, other starches, clays, other algins, other celluloses, gums, and mixtures thereof.
  • Lubricants that can be used in pharmaceutical compositions and dosage forms include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, and mixtures thereof.
  • Additional lubricants include, for example, a syloid silica gel (AEROSIL 200, manufactured by W.R. Grace Co. of Baltimore, MD), a coagulated aerosol of synthetic silica (marketed by Degussa Co. of Piano, TX), CAB O SIL (a pyrogenic silicon dioxide product sold by Cabot Co. of Boston, MA), and mixtures thereof. If used at all, lubricants are typically used in an amount of less than about 1 weight percent of the pharmaceutical compositions or dosage forms into which they are incorporated.
  • AEROSIL 200 a syloid silica gel
  • a coagulated aerosol of synthetic silica marketed by Degussa Co. of Piano, TX
  • CAB O SIL a pyrogenic silicon dioxide product sold by Cabot Co. of Boston, MA
  • lubricants are typically used in an amount of less than about 1 weight percent of the pharmaceutical compositions or dosage forms into which they are incorporated.
  • Active ingredients such as the compounds provided herein can be administered by controlled release means or by delivery devices that are well known to those of ordinary skill in the art. Examples include, but are not limited to, those described in U.S. Patent Nos.:
  • Such dosage forms can be used to provide slow or controlled release of one or more active ingredients using, for example, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions.
  • Suitable controlled release formulations known to those of ordinary skill in the art, including those described herein, can be readily selected for use with the active ingredients provided herein.
  • single unit dosage forms suitable for oral administration such as, but not limited to, tablets, capsules, gelcaps, and caplets that are adapted for controlled release.
  • controlled release pharmaceutical products have a common goal of improving drug therapy over that achieved by their non-controlled counterparts.
  • the use of an optimally designed controlled release preparation in medical treatment is characterized by a minimum of drug substance being employed to cure or control the condition in a minimum amount of time.
  • Advantages of controlled release formulations include extended activity of the drug, reduced dosage frequency, and increased subject compliance.
  • controlled release formulations can be used to affect the time of onset of action or other characteristics, such as blood levels of the drug, and can thus affect the occurrence of side ⁇ e.g., adverse) effects.
  • Controlled release of an active ingredient can be stimulated by various conditions including, but not limited to, pH, temperature, enzymes, water, or other physiological conditions or compounds.
  • the drug may be administered using intravenous infusion, an implantable osmotic pump, a transdermal patch, liposomes, or other modes of
  • a pump may be used (see, Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 (1987); Buchwald et al, Surgery 88:507 (1980); Saudek et al, N. Engl. J. Med. 321 :574 (1989)).
  • polymeric materials can be used.
  • a controlled release system can be placed in a subject at an appropriate site determined by a practitioner of skill, i.e., thus requiring only a fraction of the systemic dose (see, e.g., Goodson, Medical Applications of Controlled Release, vol. 2, pp. 115-138 (1984)).
  • the active ingredient can be dispersed in a solid inner matrix, e.g., polymethylmethacrylate, polybutylmethacrylate, plasticized or unplasticized polyvinylchloride, plasticized nylon, plasticized polyethyleneterephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinylacetate copolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonate copolymers, hydrophilic polymers such as hydrogels of esters of acrylic and methacrylic acid, collagen, cross-linked polyvinylalcohol and cross-linked partially hydrolyzed polyvinyl acetate, that is surrounded by an outer polymeric membrane, e.g., polyethylene, polypropylene, ethylene/propylene copolymers, ethyl ene/ethyl acrylate copoly
  • a solid inner matrix e.g., polymethylmethacrylate, polybutyl
  • parenteral dosage forms can be administered to subjects by various routes including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular, and intraarterial.
  • parenteral dosage forms are typically, sterile or capable of being sterilized prior to administration to a subject.
  • parenteral dosage forms include, but are not limited to, solutions ready for injection, dry products ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection, suspensions ready for injection, and emulsions.
  • Suitable vehicles that can be used to provide parenteral dosage forms are well known to those skilled in the art. Examples include, but are not limited to: Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
  • aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection
  • Transdermal, topical, and mucosal dosage forms include, but are not limited to, ophthalmic solutions, sprays, aerosols, creams, lotions, ointments, gels, solutions, emulsions, suspensions, or other forms known to one of skill in the art. See, e.g., Remington's Pharmaceutical Sciences, 16 th , 18th and 20 th eds., Mack Publishing, Easton PA (1980, 1990 & 2000); and Introduction to
  • Dosage forms suitable for treating mucosal tissues within the oral cavity can be formulated as mouthwashes or as oral gels.
  • transdermal dosage forms include "reservoir type” or “matrix type” patches, which can be applied to the skin and worn for a specific period of time to permit the penetration of a desired amount of active ingredients.
  • Suitable excipients (e.g., carriers and diluents) and other materials that can be used to provide transdermal, topical, and mucosal dosage forms encompassed herein are well known to those skilled in the pharmaceutical arts, and depend on the particular tissue to which a given pharmaceutical composition or dosage form will be applied.
  • excipients include, but are not limited to, water, acetone, ethanol, ethylene glycol, propylene glycol, butane 1,3 diol, isopropyl myristate, isopropyl palmitate, mineral oil, and mixtures thereof to form lotions, tinctures, creams, emulsions, gels or ointments, which are nontoxic and pharmaceutically acceptable.
  • Moisturizers or humectants can also be added to pharmaceutical compositions and dosage forms if desired. Examples of such additional ingredients are well known in the art. See, e.g., Remington's Pharmaceutical Sciences, 16 th , 18th and 20 th eds., Mack Publishing, Easton PA (1980, 1990 & 2000).
  • penetration enhancers can be used to assist in delivering the active ingredients to the tissue.
  • Suitable penetration enhancers include, but are not limited to: acetone; various alcohols such as ethanol, oleyl, and tetrahydrofuryl; alkyl sulfoxides such as dimethyl sulfoxide; dimethyl acetamide; dimethyl formamide; polyethylene glycol; pyrrolidones such as polyvinylpyrrolidone; Kollidon grades (Povidone, Polyvidone); urea; and various water soluble or insoluble sugar esters such as Tween 80 (polysorbate 80) and Span 60 (sorbitan
  • the pH of a pharmaceutical composition or dosage form, or of the tissue to which the pharmaceutical composition or dosage form is applied may also be adjusted to improve delivery of one or more active ingredients.
  • the polarity of a solvent carrier, its ionic strength, or tonicity can be adjusted to improve delivery.
  • Compounds such as stearates can also be added to pharmaceutical compositions or dosage forms to advantageously alter the hydrophilicity or lipophilicity of one or more active ingredients so as to improve delivery.
  • stearates can serve as a lipid vehicle for the formulation, as an emulsifying agent or surfactant, and as a delivery enhancing or penetration enhancing agent.
  • Different salts, hydrates or solvates of the active ingredients can be used to further adjust the properties of the resulting composition.
  • doses are from about 1 to about 1000 mg per day for an adult, or from about 5 to about 250 mg per day or from about 10 to 50 mg per day for an adult. In certain embodiments, doses are from about 5 to about 400 mg per day or 25 to 200 mg per day per adult. In certain embodiments, dose rates of from about 50 to about 500 mg per day are also contemplated.
  • kits for treating or preventing an HCV infection in a subject by administering, to a subject in need thereof, an effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof.
  • the amount of the compound or composition which will be effective in the prevention or treatment of a disorder or one or more symptoms thereof will vary with the nature and severity of the disease or condition, and the route by which the active ingredient is administered.
  • the frequency and dosage will also vary according to factors specific for each subject depending on the specific therapy (e.g., therapeutic or prophylactic agents) administered, the severity of the disorder, disease, or condition, the route of administration, as well as age, body, weight, response, and the past medical history of the subject.
  • Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems.
  • exemplary doses of a composition include milligram or microgram amounts of the active compound per kilogram of subject or sample weight (e.g., about 10 micrograms per kilogram to about 50 milligrams per kilogram, about 100 micrograms per kilogram to about 25 milligrams per kilogram, or about 100 microgram per kilogram to about 10 milligrams per kilogram).
  • the dosage administered to a subject is 0.140 mg/kg to 3 mg/kg of the subject's body weight, based on weight of the active compound.
  • the dosage administered to a subject is between 0.20 mg/kg and 2.00 mg/kg, or between 0.30 mg/kg and 1.50 mg/kg of the subject's body weight.
  • the recommended daily dose range of a composition provided herein for the conditions described herein lie within the range of from about 0.1 mg to about 1000 mg per day, given as a single once-a-day dose or as divided doses throughout a day.
  • the daily dose is administered twice daily in equally divided doses.
  • a daily dose range should be from about 10 mg to about 200 mg per day, in other embodiments, between about 10 mg and about 150 mg per day, in further embodiments, between about 25 and about 100 mg per day. It may be necessary to use dosages of the active ingredient outside the ranges disclosed herein in some cases, as will be apparent to those of ordinary skill in the art.
  • the clinician or treating physician will know how and when to interrupt, adjust, or terminate therapy in conjunction with subject response.
  • the dosage of the composition provided herein, based on weight of the active compound, administered to prevent, treat, manage, or ameliorate a disorder, or one or more symptoms thereof in a subject is 0.1 mg/kg, 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 6 mg/kg, 10 mg/kg, or 15 mg/kg or more of a subject's body weight.
  • the dosage of the composition or a composition provided herein administered to prevent, treat, manage, or ameliorate a disorder, or one or more symptoms thereof in a subject is a unit dose of 0.1 mg to 200 mg, 0.1 mg to 100 mg, 0.1 mg to 50 mg, 0.1 mg to 25 mg, 0.1 mg to 20 mg, 0.1 mg to 15 mg, 0.1 mg to 10 mg, 0.1 mg to 7.5 mg, 0.1 mg to 5 mg, 0.1 to 2.5 mg, 0.25 mg to 20 mg, 0.25 to 15 mg, 0.25 to 12 mg, 0.25 to 10 mg, 0.25 mg to 7.5 mg, 0.25 mg to 5 mg, 0.5 mg to 2.5 mg, 1 mg to 20 mg, 1 mg to 15 mg, 1 mg to 12 mg, 1 mg to 10 mg, 1 mg to 7.5 mg, 1 mg to 5 mg, or 1 mg to 2.5 mg.
  • treatment or prevention can be initiated with one or more loading doses of a compound or composition provided herein followed by one or more maintenance doses.
  • the loading dose can be, for instance, about 60 to about 400 mg per day, or about 100 to about 200 mg per day for one day to five weeks.
  • the loading dose can be followed by one or more maintenance doses.
  • each maintenance does is, independently, about from about 10 mg to about 200 mg per day, between about 25 mg and about 150 mg per day, or between about 25 and about 80 mg per day.
  • Maintenance doses can be administered daily and can be administered as single doses, or as divided doses.
  • a dose of a compound or composition provided herein can be administered to achieve a steady-state concentration of the active ingredient in blood or serum of the subject.
  • the steady-state concentration can be determined by measurement according to techniques available to those of skill or can be based on the physical
  • a sufficient amount of a compound or composition provided herein is administered to achieve a steady- state concentration in blood or serum of the subject of from about 300 to about 4000 ng/mL, from about 400 to about 1600 ng/mL, or from about 600 to about 1200 ng/mL.
  • loading doses can be administered to achieve steady-state blood or serum concentrations of about 1200 to about 8000 ng/mL, or about 2000 to about 4000 ng/mL for one to five days.
  • maintenance doses can be administered to achieve a steady- state concentration in blood or serum of the subject of from about 300 to about 4000 ng/mL, from about 400 to about 1600 ng/mL, or from about 600 to about 1200 ng/mL.
  • administration of the same composition may be repeated and the administrations may be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months.
  • administration of the same prophylactic or therapeutic agent may be repeated and the administration may be separated by at least at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months.
  • unit dosages comprising a compound, or a pharmaceutically acceptable salt thereof, in a form suitable for administration. Such forms are described in detail herein.
  • the unit dosage comprises 1 to 1000 mg, 5 to 250 mg or 10 to 50 mg active ingredient.
  • the unit dosages comprise about 1, 5, 10, 25, 50, 100, 125, 250, 500 or 1000 mg active ingredient.
  • Such unit dosages can be prepared according to techniques familiar to those of skill in the art.
  • the dosages of the second agents are to be used in the combination therapies provided herein. In certain embodiments, dosages lower than those which have been or are currently being used to prevent or treat HCV infection are used in the combination therapies provided herein.
  • the recommended dosages of second agents can be obtained from the knowledge of those of skill. For those second agents that are approved for clinical use, recommended dosages are described in, for example, Hardman et ah, eds., 1996, Goodman & Gilman's The Pharmacological Basis Of Basis Of Therapeutics 9 th Ed, Mc-Graw-Hill, New York; Physician's Desk Reference (PDR) 57 Ed., 2003, Medical Economics Co., Inc., Montvale, NJ, which are incorporated herein by reference in its entirety.
  • the therapies are administered less than 5 minutes apart, less than 30 minutes apart, 1 hour apart, at about 1 hour apart, at about 1 to about 2 hours apart, at about 2 hours to about 3 hours apart, at about 3 hours to about 4 hours apart, at about 4 hours to about 5 hours apart, at about 5 hours to about 6 hours apart, at about 6 hours to about 7 hours apart, at about 7 hours to about 8 hours apart, at about 8 hours to about 9 hours apart, at about 9 hours to about 10 hours apart, at about 10 hours to about 1 1 hours apart, at about 1 1 hours to about 12 hours apart, at about 12 hours to 18 hours apart, 18 hours to 24 hours apart, 24 hours to 36 hours apart, 36 hours to 48 hours apart, 48 hours to 52 hours apart, 52 hours to 60 hours apart, 60 hours to 72 hours apart, 72 hours to 84 hours apart, 84 hours to 96 hours apart, or 96 hours to 120 hours apart.
  • the therapies are administered no more than 24 hours apart,
  • the compound provided herein and the second agent are administered at about 2 to 4 days apart, at about 4 to 6 days apart, at about 1 week part, at about 1 to 2 weeks apart, or more than 2 weeks apart.
  • administration of the same agent may be repeated and the administrations may be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months.
  • administrations may be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months.
  • administration of the same agent may be repeated and the administration may be separated by at least at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months.
  • a compound provided herein and a second agent are administered to a patient, for example, a mammal, such as a human, in a sequence and within a time interval such that the compound provided herein can act together with the other agent to provide an increased benefit than if they were administered otherwise.
  • the second active agent can be administered at the same time or sequentially in any order at different points in time; however, if not administered at the same time, they should be administered sufficiently close in time so as to provide the desired therapeutic or prophylactic effect.
  • the compound provided herein and the second active agent exert their effect at times which overlap.
  • Each second active agent can be administered separately, in any appropriate form and by any suitable route.
  • the compound provided herein is administered before, concurrently or after administration of the second active agent.
  • the compound provided herein and the second agent are cyclically administered to a patient.
  • Cycling therapy involves the administration of a first agent (e.g., a first prophylactic or therapeutic agents) for a period of time, followed by the administration of a second agent and/or third agent (e.g., a second and/or third prophylactic or therapeutic agents) for a period of time and repeating this sequential administration. Cycling therapy can reduce the development of resistance to one or more of the therapies, avoid or reduce the side effects of one of the therapies, and/or improve the efficacy of the treatment.
  • a first agent e.g., a first prophylactic or therapeutic agents
  • second agent and/or third agent e.g., a second and/or third prophylactic or therapeutic agents
  • the compound provided herein and the second active agent are administered in a cycle of less than about 3 weeks, about once every two weeks, about once every 10 days or about once every week.
  • One cycle can comprise the administration of a compound provided herein and the second agent by infusion over about 90 minutes every cycle, about 1 hour every cycle, about 45 minutes every cycle.
  • Each cycle can comprise at least 1 week of rest, at least 2 weeks of rest, at least 3 weeks of rest.
  • the number of cycles administered is from about 1 to about 12 cycles, more typically from about 2 to about 10 cycles, and more typically from about 2 to about 8 cycles.
  • courses of treatment are administered concurrently to a patient, i.e., individual doses of the second agent are administered separately yet within a time interval such that the compound provided herein can work together with the second active agent.
  • one component can be administered once per week in combination with the other components that can be administered once every two weeks or once every three weeks.
  • the dosing regimens are carried out concurrently even if the
  • therapeutics are not administered simultaneously or during the same day.
  • the second agent can act additively or synergistically with the compound provided herein.
  • the compound provided herein is administered concurrently with one or more second agents in the same pharmaceutical composition.
  • a compound provided herein is administered concurrently with one or more second agents in separate pharmaceutical compositions.
  • a compound provided herein is administered prior to or subsequent to administration of a second agent.
  • administration of a compound provided herein and a second agent by the same or different routes of administration, e.g., oral and parenteral.
  • the second active agent when the compound provided herein is administered concurrently with a second agent that potentially produces adverse side effects including, but not limited to, toxicity, can advantageously be administered at a dose that falls below the threshold that the adverse side effect is elicited.
  • kits for use in methods of treatment of a liver disorder such as HCV infections.
  • the kits can include a compound or composition provided herein, a second agent or composition, and instructions providing information to a health care provider regarding usage for treating the disorder. Instructions may be provided in printed form or in the form of an electronic medium such as a floppy disc, CD, or DVD, or in the form of a website address where such instructions may be obtained.
  • a unit dose of a compound or composition provided herein, or a second agent or composition can include a dosage such that when administered to a subject, a therapeutically or prophylactically effective plasma level of the compound or composition can be maintained in the subject for at least 1 days.
  • a compound or composition can be included as a sterile aqueous pharmaceutical composition or dry powder (e.g., lyophilized) composition.
  • suitable packaging includes a solid matrix or material customarily used in a system and capable of holding within fixed limits a compound provided herein and/or a second agent suitable for administration to a subject.
  • materials include glass and plastic (e.g., polyethylene, polypropylene, and polycarbonate) bottles, vials, paper, plastic, and plastic-foil laminated envelopes and the like. If e-beam sterilization techniques are employed, the packaging should have sufficiently low density to permit sterilization of the contents.
  • provided herein are methods for the treatment and/or prophylaxis of a host infected with Flaviviridae that includes the administration of an effective amount of a compounds provided herein, or a pharmaceutically acceptable salt thereof.
  • methods for treating an HCV infection in a subject encompass the step of administering to the subject in need thereof an amount of a compound effective for the treatment or prevention of an HCV infection in combination with a second agent effective for the treatment or prevention of the infection.
  • the compound can be any compound as described herein, and the second agent can be any second agent described in the art or herein.
  • the compound is in the form of a pharmaceutical composition or dosage form, as described elsewhere herein.
  • Flaviviridae that can be treated are discussed generally in Fields Virology, Editors: Fields, B. N., Knipe, D. M., and Howley, P. M., Lippincott-Raven Publishers, Philadelphia, PA, Chapter 31, 1996.
  • the Flaviviridae is HCV.
  • the Flaviviridae is a flavivirus or pestivirus.
  • flaviviruses include, without limitation: Absettarov, Alfuy, AIN, Aroa, Bagaza, Banzi, Bouboui, Bussuquara, Cacipacore, Carey Island, Dakar bat, Dengue 1, Dengue 2, Dengue 3, Dengue 4, Edge Hill, Entebbe bat, Gadgets Gully, Hanzalova, Hypr, Ilheus, Israel turkey meningoencephalitis, Japanese encephalitis, Jugra, Jutiapa, Kadam, Karshi, Kedougou, Kokobera, Koutango, Kumlinge, Kunjin, Kyasanur Forest disease, Langat, Louping ill, Meaban, Modoc, Montana myotis leukoencephalitis, Murray valley encephalitis, Naranjal, Negishi, Ntaya, Omsk hemorrhagic fever, Phnom-Penh bat, Powassan, Rio Bravo, Rocio, Royal Farm, Russian spring-summer encephalitis, Saboya
  • Pestiviruses that can be treated are discussed generally in Fields Virology, Editors: Fields, B. N., Knipe, D. M., and Howley, P. M., Lippincott-Raven Publishers, Philadelphia, PA, Chapter 33, 1996.
  • Specific pestiviruses include, without limitation: bovine viral diarrhea virus (“BVDV”), classical swine fever virus (“CSFV,” also called hog cholera virus), and border disease virus (“BDV”).
  • BVDV bovine viral diarrhea virus
  • CSFV classical swine fever virus
  • BDV border disease virus
  • the subject can be any subject infected with, or at risk for infection with, HCV. Infection or risk for infection can be determined according to any technique deemed suitable by the practitioner of skill in the art. In certain embodiments, subjects are humans infected with HCV.
  • the subject has never received therapy or prophylaxis for an HCV infection.
  • the subject has previously received therapy or prophylaxis for an HCV infection.
  • the subject has not responded to an HCV therapy.
  • the subject can be a subject that received therapy but continued to suffer from viral infection or one or more symptoms thereof.
  • the subject can be a subject that received therapy but failed to achieve a sustained virologic response.
  • the subject has received therapy for an HCV infection but has failed to show, for example, a 2 logio decline in HCV R A levels after 12 weeks of therapy. It is believed that subjects who have not shown more than 2 logio reduction in serum HCV RNA after 12 weeks of therapy have a 97-100% chance of not responding.
  • the subject is a subject that discontinued an HCV therapy because of one or more adverse events associated with the therapy.
  • the subject is a subject where current therapy is not indicated.
  • certain therapies for HCV are associated with neuropsychiatric events.
  • Interferon (IFN)-alfa plus ribavirin is associated with a high rate of depression.
  • Depressive symptoms have been linked to a worse outcome in a number of medical disorders. Life-threatening or fatal neuropsychiatric events, including suicide, suicidal and homicidal ideation, depression, relapse of drug
  • Interferon-induced depression is a limitation for the treatment of chronic hepatitis C, especially for subjects with psychiatric disorders.
  • Psychiatric side effects are common with interferon therapy and responsible for about 10% to 20% of discontinuations of current therapy for HCV infection.
  • methods of treating or preventing HCV infection in subjects where a neuropsychiatric event, such as depression, or risk of such indicates dose reduction of current HCV therapy.
  • a hemoglobinopathy for instance thalassemia major subjects and sickle-cell anemia subjects
  • the subject has received an HCV therapy and discontinued that therapy prior to administration of a method provided herein. In further embodiments, the subject has received therapy and continues to receive that therapy along with administration of a method provided herein.
  • the methods can be co-administered with other therapy for HBC and/or HCV according to the judgment of one of skill in the art. In certain embodiments, the methods or compositions provided herein can be co-administered with a reduced dose of the other therapy for HBC and/or HCV.
  • the subject can be a subject that has failed to respond to treatment with one or more agents selected from the group consisting of interferon, interferon a, pegylated interferon a, interferon plus ribavirin, interferon a plus ribavirin and pegylated interferon a plus ribavirin.
  • the subject can be a subject that has responded poorly to treatment with one or more agents selected from the group consisting of interferon, interferon a, pegylated interferon a, interferon plus ribavirin, interferon a plus ribavirin and pegylated interferon a plus ribavirin.
  • a pro-drug form of ribavirin such as taribavirin, may also be used.
  • the subject has, or is at risk for, co-infection of HCV with HIV.
  • 30% of HIV subjects are co-infected with HCV and evidence indicates that people infected with HIV have a much more rapid course of their hepatitis C infection.
  • the methods provided herein can be used to treat or prevent HCV infection in such subjects. It is believed that elimination of HCV in these subjects will lower mortality due to end-stage liver disease. Indeed, the risk of progressive liver disease is higher in subjects with severe AIDS-defining immunodeficiency than in those without.
  • kits for treating or preventing HIV infection and HCV infection in subjects in need thereof are provided.
  • the compounds or compositions are administered to a subject following liver transplant.
  • Hepatitis C is a leading cause of liver transplantation in the U.S., and many subjects that undergo liver transplantation remain HCV positive following transplantation.
  • Compounds can be assayed for HCV activity according to any assay known to those of skill in the art.
  • compounds can be assayed for accumulation in liver cells of a subject according to any assay known to those of skill in the art.
  • a compound can be administered to the subject, and a liver cell of the subject can be assayed for the compound or a derivative thereof, e.g. a nucleoside, nucleoside phosphate or nucleoside triphosphate derivative thereof.
  • a 3 ',5 '-cyclic phosphate prodrug compound is
  • nucleoside triphosphate levels delivered intracellular ly are measured, to indicate delivery of the compound and triphosphorylation in the cell.
  • the levels of intracellular nucleoside triphosphate can be measured using analytical techniques known in the art. Methods of detecting ddATP are described herein below by way of example, but other nucleoside triphosphates can be readily detected using the appropriate controls, calibration samples and assay techniques.
  • ddATP concentrations are measured in a sample by comparison to calibration standards made from control samples.
  • the ddATP concentrations in a sample can be measured using an analytical method such as HPLC LC MS.
  • a test sample is compared to a calibration curve created with known
  • the samples are manipulated to remove impurities such as salts (Na + , K + , etc.) before analysis.
  • the lower limit of quantitation is about - 0.2 pmol / mL for hepatocyte cellular extracts particularly where reduced salt is present.
  • the method allows successfully measuring triphosphate nucleotides formed at levels of 1 - 10,000 pmol per million cells in e.g. cultured hepatocytes and HepG2 cells.
  • the compounds and compositions provided herein are useful in methods of treatment of a liver disorder, that comprise further administration of a second agent effective for the treatment of the disorder, such as HCV infection in a subject in need thereof.
  • a second agent effective for the treatment of the disorder such as HCV infection in a subject in need thereof.
  • the second agent can be any agent known to those of skill in the art to be effective for the treatment of the disorder, including those currently approved by the FDA.
  • a compound provided herein is administered in
  • a second agent is administered in combination with two second agents.
  • a second agent is administered in combination with two or more second agents.
  • the term "in combination” includes the use of more than one therapy (e.g., one or more prophylactic and/or therapeutic agents).
  • the use of the term “in combination” does not restrict the order in which therapies ⁇ e.g., prophylactic and/or therapeutic agents) are administered to a subject with a disorder.
  • a first therapy ⁇ e.g., a prophylactic or therapeutic agent such as a compound provided herein
  • a prophylactic or therapeutic agent such as a compound provided herein
  • a second therapy ⁇ e.g., a pro
  • the term "synergistic” includes a combination of a compound provided herein and another therapy ⁇ e.g. , a prophylactic or therapeutic agent) which has been or is currently being used to prevent, manage or treat a disorder, which is more effective than the additive effects of the therapies.
  • a synergistic effect of a combination of therapies ⁇ e.g., a combination of prophylactic or therapeutic agents) permits the use of lower dosages of one or more of the therapies and/or less frequent administration of said therapies to a subject with a disorder.
  • a therapy e.g., a prophylactic or therapeutic agent
  • a synergistic effect can result in improved efficacy of agents in the prevention or treatment of a disorder.
  • a synergistic effect of a combination of therapies e.g., a combination of prophylactic or therapeutic agents
  • the active compounds provided herein can be administered in combination or alternation with another therapeutic agent, in particular an anti-HCV agent.
  • combination therapy effective dosages of two or more agents are administered together, whereas in alternation or sequential-step therapy, an effective dosage of each agent is administered serially or sequentially.
  • the dosages given will depend on absorption, inactivation and excretion rates of the drug as well as other factors known to those of skill in the art. It is to be noted that dosage values will also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens and schedules should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions.
  • an anti-HCV (or anti-pestivirus or anti-flavivirus) compound that exhibits an EC 5 o of 10-15 ⁇ . In certain embodiments, less than 1-5 ⁇ , is desirable.
  • Non- limiting examples of second agents include:
  • HCV Protease inhibitors examples include Medivir HCV Protease Inhibitor (HCV-PI or TMC435) (Medivir/Tibotec); MK-7009 (Merck), RG7227 (ITMN-191)
  • narlaprevir SCH900518 (Schering), narlaprevir SCH900518 (Schering/Merck), ABT-450 (Abbott/Enanta), ACH-1625 (Achillion), BI 201335 (Boehringer Ingelheim), PHX1766 (Phenomix), VX-500 (Vertex) and telaprevir (VX-950) (Vertex).
  • protease inhibitors include substrate-based NS3 protease inhibitors (Attwood et al, Antiviral peptide derivatives, PCT WO 98/22496, 1998; Attwood et al., Antiviral Chemistry and Chemotherapy 1999, 10, 259-273; Attwood et al., Preparation and use of amino acid derivatives as anti-viral agents, German Patent Pub.
  • SCH 351633 isolated from the fungus Penicillium griseofulvum, was identified as a protease inhibitor (Chu M. et al., Bioorganic and Medicinal Chemistry Letters 9: 1949-1952).
  • Eglin c isolated from leech, is a potent inhibitor of several serine proteases such as S. griseus proteases A and B, a-chymotrypsin, chymase and subtilisin. Qasim M.A. et al, Biochemistry 36: 1598-1607, 1997.
  • U.S. patents disclosing protease inhibitors for the treatment of HCV include, for example, U.S. Patent No. 6,004,933 to Spruce et al, which discloses a class of cysteine protease inhibitors for inhibiting HCV endopeptidase 2; U.S. Patent No. 5,990,276 to Zhang et al, which discloses synthetic inhibitors of hepatitis C virus NS3 protease; U.S. Patent No. 5,538,865 to Reyes et a; WO 02/008251 to Corvas International, Inc., and US7,169,760, US2005/176648, WO 02/08187 and WO 02/008256 to Schering Corporation.
  • HCV inhibitor tripeptides are disclosed in US Patent Nos. 6,534,523, 6,410,531, and 6,420,380 to Boehringer Ingelheim and WO 02/060926 to Bristol Myers Squibb.
  • Diaryl peptides as NS3 serine protease inhibitors of HCV are disclosed in WO 02/48172 and US 6,911,428 to Schering Corporation.
  • Imidazoleidinones as NS3 serine protease inhibitors of HCV are disclosed in WO 02/08198 and US 6,838,475 to Schering Corporation and WO 02/48157 and US 6,727,366 to Bristol Myers Squibb.
  • HCV protease inhibitors include US 6,872,805 (Bristol- Myers Squibb); WO 2006000085 (Boehringer Ingelheim); US 7,208,600 (Vertex); US 2006/0046956 (Schering-Plough); WO 2007/001406 (Chiron); US 2005/0153877; WO
  • Thiazolidine derivatives which show relevant inhibition in a reverse-phase HPLC assay with an NS3/4A fusion protein and NS5A/5B substrate (Sudo K. et al., Antiviral Research, 1996, 32, 9-18), especially compound RD-1-6250, possessing a fused cinnamoyl moiety substituted with a long alkyl chain, RD4 6205 and RD4 6193;
  • a phenanthrenequinone possessing activity against protease in a SDS-PAGE and autoradiography assay isolated from the fermentation culture broth of Streptomyces sp., SCH 68631 (Chu M. et al, Tetrahedron Letters, 1996, 37, 7229-7232), and SCH 351633, isolated from the fungus Penicillium griseofulvum, which demonstrates activity in a scintillation proximity assay (Chu M. et al., Bioorganic and Medicinal Chemistry Letters 9, 1949-1952);
  • Helicase inhibitors (Diana G.D. et al., Compounds, compositions and methods for treatment of hepatitis C, U.S. Pat. No. 5,633,358; Diana G.D. et al., Piperidine derivatives, pharmaceutical compositions thereof and their use in the treatment of hepatitis C, PCT WO 97/36554);
  • HCV polymerase inhibitors including nucleoside and non-nucleoside polymerase inhibitors, such as ribavirin, viramidine, clemizole, filibuvir (PF-00868554), HCV POL, NM 283 (valopicitabine), MK-0608, 7-Fluoro-MK-0608, MK-3281, IDX-375, ABT-072, ABT- 333, ANA598, BI 207127, GS 9190, PSI-6130, R1626, PSI-6206, PSI-938, PSI-7851, PSI- 7977, RG1479, RG7128, HCV-796 VCH-759 or VCH-916.
  • nucleoside and non-nucleoside polymerase inhibitors such as ribavirin, viramidine, clemizole, filibuvir (PF-00868554), HCV POL, NM 283 (valopicitabine), MK-0608
  • Interfering RNA (iRNA) based antivirals including short interfering RNA (siRNA) based antivirals, such as Sirna-034 and others described in International Patent Publication Nos. WO/03/070750 and WO 2005/012525, and US Patent Publication No. US 2004/0209831.
  • iRNA Interfering RNA
  • siRNA short interfering RNA
  • S-ODN Antisense phosphorothioate oligodeoxynucleotides
  • NCR non-coding region
  • nucleotides 326-348 comprising the 3' end of the NCR and nucleotides 371-388 located in the core coding region of the HCV RNA (Alt M. et al, Archives of
  • Inhibitors of IRES-dependent translation (Ikeda N et al. , Agent for the prevention and treatment of hepatitis C, Japanese Patent Pub. JP-08268890; Kai Y. et al., Prevention and treatment of viral diseases, Japanese Patent Pub. JP-10101591);
  • HCV entry inhibitors such as celgosivir (MK-3253) (MIGENIX Inc.), SP-30 (Samaritan Pharmaceuticals), ITX4520 (iTherX), ITX5061 (iTherX), PRO-206 (Progenies Pharmaceuticals) and other entry inhibitors by Progenies Pharmaceuticals, e.g., as disclosed in U.S. Patent Publication No. 2006/0198855.
  • Ribozymes such as nuclease-resistant ribozymes (Maccjak, D. J. et al, Hepatology 1999, 30, abstract 995) and those disclosed in U.S. Patent No. 6,043,077 to Barber et al, and U.S. Patent Nos. 5,869,253 and 5,610,054 to Draper et al; and
  • the compounds provided herein can be administered in combination with any of the compounds described by Idenix Pharmaceuticals in International Publication Nos. WO 01/90121, WO 01/92282, WO 2004/003000, 2004/002422 and WO 2004/002999.
  • Other compounds that can be used as second agents include 1-amino- alkylcyclohexanes (U.S. Patent No. 6,034,134 to Gold et al), alkyl lipids (U.S. Pat. No.
  • benzenedicarboxamides U.S. Pat. No. 5,633,388 to Diana et al
  • polyadenylic acid derivatives U.S. Pat. No. 5,496,546 to Wang et al
  • 2',3'-dideoxyinosine U.S. Pat. No. 5,026,687 to Yarchoan et al.
  • benzimidazoles U.S. Pat. No. 5,891,874 to Colacino et al.
  • plant extracts U.S. Patent No. 5,837,257 to Tsai et al, U.S. Patent No. 5,725,859 to Omer et al, and U.S. Patent No. 6,056,961
  • piperidines U.S. Patent No. 5,830,905 to Diana et al.
  • a compound of Formula I-VI or a composition comprising a compound of Formula I-VI is administered in combination or alternation with a second antiviral agent selected from the group consisting of an interferon, a nucleotide analogue, a polymerase inhibitor, an NS3 protease inhibitor, an NS5A inhibitor, an entry inhibitor, a non- nucleoside polymerase inhibitor, a cyclosporine immune inhibitor, an NS4A antagonist, an NS4B-RNA binding inhibitor, a locked nucleic acid mRNA inhibitor, a cyclophilin inhibitor, and combinations thereof.
  • a second antiviral agent selected from the group consisting of an interferon, a nucleotide analogue, a polymerase inhibitor, an NS3 protease inhibitor, an NS5A inhibitor, an entry inhibitor, a non- nucleoside polymerase inhibitor, a cyclosporine immune inhibitor, an NS4A antagonist, an NS4B-RNA binding inhibitor, a
  • one or more compounds provided herein can be administered in combination or alternation with an anti-hepatitis C virus interferon, such as Intron A ® (interferon alfa-2b) and; Roferon A ® (Recombinant interferon alfa-2a), Infergen ® (consensus interferon; interferon alfacon-1), PEG-lntron ® (pegylated interferon alfa-2b), and Pegasys ® (pegylated interferon alfa-2a).
  • an anti-hepatitis C virus interferon such as Intron A ® (interferon alfa-2b) and; Roferon A ® (Recombinant interferon alfa-2a), Infergen ® (consensus interferon; interferon alfacon-1), PEG-lntron ® (pegylated interferon alfa-2b), and Pegasys ® (pegylated interferon alfa
  • one or more compounds provided herein can be administered in combination or alternation with ribavirin, in combination or alternation with an anti-hepatitis C virus interferon, and in combination or alternation with an anti-hepatitis C virus protease inhibitor. In certain embodiments, one or more compounds provided herein can be administered in combination or alternation with ribavirin. In certain embodiments, one or more compounds provided herein can be administered in combination or alternation with an anti-hepatitis C virus interferon and without ribavirin. In certain embodiments, one or more compounds provided herein can be administered in combination or alternation with an anti-hepatitis C virus interferon, in combination or alternation with an anti-hepatitis C virus protease inhibitor, and without ribavirin.
  • the anti-hepatitis C virus interferon is infergen, IL-29 (PEG-Interferon lambda), R7025 (Maxy-alpha), Belerofon, Oral Interferon alpha, BLX-883 (Locteron), omega interferon, multiferon, medusa interferon, Albuferon or REBIF ® .
  • one or more compounds provided herein can be administered in combination or alternation with an anti-hepatitis C virus polymerase inhibitor, such as ribavirin, viramidine, HCV POL, NM 283 (valopicitabine), MK-0608, 7-Fluoro-MK- 0608, PSI-6130, R1626, PSI-6206, PSI-938, R1479, HCV-796, VX-950 (Telaprevir, Vertex), GS 9190 N (Gilead), GS 9256 (Gilead), PSI-7792 (BMS), BI 207127 (BI), R7128 (Roche), or PSI-7977 (Pharmasset), PSI-938 (Pharmasset), VX-222 (Vertex), ALS-2200 (Vertex), ALS- 2158 (Vertex), MK-0608 (Merck), TMC649128 (Medivir), PF-868554 (Pfizer), PF-487
  • the one or more compounds provided herein can be administered in combination with ribavarin and an anti-hepatitis C virus interferon, such as Intron A ® (interferon alfa-2b) and Pegasys ® (Peginterferon alfa-2a); Roferon A ® (Recombinant interferon alfa-2a), Infergen ® (consensus interferon; interferon alfacon-1), PEG-Intron ® (pegylated interferon alfa-2b), Zalbin (albinterferon alfa-2b), omega interferon, pegylated interferon lambda, and Pegasys ® (pegylated interferon alfa-2a).
  • Intron A ® interferon alfa-2b
  • Pegasys ® Peginterferon alfa-2a
  • Roferon A ® Recombinant interferon alfa-2a
  • Infergen ® consensus inter
  • one or more compounds provided herein can be administered in combination or alternation with an anti-hepatitis C virus protease inhibitor such as ITMN-191, SCH 503034 (bocepravir), VX950 (telaprevir), VX985, VX500, VX813, PHX1766, BMS-650032, GS 9256, BI 201335, IDX320, R7227, MK-7009 (vaniprevir), TMC435, BMS-791325, ACH-1625, ACH-2684, ABT-450, AVL-181, or Medivir HCV Protease Inhibitor.
  • an anti-hepatitis C virus protease inhibitor such as ITMN-191, SCH 503034 (bocepravir), VX950 (telaprevir), VX985, VX500, VX813, PHX1766, BMS-650032, GS 9256, BI 201335, IDX320, R7227, MK-7009 (vaniprevir), TMC435, B
  • one or more compounds provided herein can be administered in combination or alternation with an HCV NS5A inhibitor, such as BMS-790052 (daclatasvir , Bristol-Myers Squibb), PPI-461 (Presidio Pharmaceuticals), PPI-1301 (Presidio Pharmaceuticals), IDX-719 (Idenix Pharmaceuticals), AZD7295 (Arrow Therapeutics, AstraZeneca), EDP-239 (Enanta), ACH-2928 (Achillion), ACH-3102 (Achillion), ABT-267 (Abbott), or GS-5885 (Gilead).
  • an HCV NS5A inhibitor such as BMS-790052 (daclatasvir , Bristol-Myers Squibb), PPI-461 (Presidio Pharmaceuticals), PPI-1301 (Presidio Pharmaceuticals), IDX-719 (Idenix Pharmaceuticals), AZD7295 (Arrow Therapeutics, AstraZeneca), EDP-239 (Enanta), ACH-2928 (A
  • one or more compounds provided herein can be administered in combination or alternation with an anti-hepatitis C virus vaccine, such as TG4040, PeviPROTM, CGI-5005, HCV/MF59, GV1001, IC41, GNI-103, GenPhar HCV vaccine, C-Vaxin, CSL123, Hepavaxx C, ChronVac-C® or INNO0101 (El).
  • an anti-hepatitis C virus vaccine such as TG4040, PeviPROTM, CGI-5005, HCV/MF59, GV1001, IC41, GNI-103, GenPhar HCV vaccine, C-Vaxin, CSL123, Hepavaxx C, ChronVac-C® or INNO0101 (El).
  • one or more compounds provided herein can be administered in combination or alternation with an anti-hepatitis C virus monoclonal antibody, such as MBL-HCV1, AB68 or XTL-6865 (formerly HepX-C); or an anti-hepatitis C virus polyclonal antibody, such as cicavir.
  • an anti-hepatitis C virus monoclonal antibody such as MBL-HCV1, AB68 or XTL-6865 (formerly HepX-C)
  • an anti-hepatitis C virus polyclonal antibody such as cicavir.
  • one or more compounds provided herein can be administered in combination or alternation with an anti-hepatitis C virus immunomodulator, such as Zadaxin ® (thymalfasin), SCV-07, NOV-205 or Oglufanide.
  • an anti-hepatitis C virus immunomodulator such as Zadaxin ® (thymalfasin), SCV-07, NOV-205 or Oglufanide.
  • one or more compounds provided herein can be administered in combination or alternation with cyclophilin inhibitor, such as Enanta cyclophilin binder, SCY-635, or Debio-025.
  • cyclophilin inhibitor such as Enanta cyclophilin binder, SCY-635, or Debio-025.
  • one or more compounds provided herein can be administered in combination or alternation with Nexavar, doxorubicin, PI-88, amantadine, JBK-122, VGX-410C, MX-3253 (Ceglosivir), Suvus (BIVN-401 or virostat), PF-03491390 (formerly IDN-6556), G126270, UT-231B, DEBIO-025, EMZ702, ACH-0137171, MitoQ, ANA975, AVI-4065, Bavituxinab (Tarvacin), Alinia (nitrazoxanide) or PYN17.
  • one or more compounds provided herein can be administered in combination or alternation with telaprevir, bocepravir, interferon alfacon-1, interferon alfa-2b, pegylated interferon alpha 2a, pegylated interferon alpha 2b, ribavirin, or combinations thereof.
  • one or more compounds provided herein can be administered in combination or alternation with a protease inhibitor. In certain embodiments, one or more compounds provided herein can be administered in combination or alternation with telaprevir. In certain embodiments, one or more compounds provided herein can be administered in combination or alternation with bocepravir. [00313] In certain embodiments, one or more compounds provided herein can be administered in combination or alternation with a protease inhibitor and in combination or alternation with ribavirin. In certain embodiments, one or more compounds provided herein can be administered in combination or alternation with telaprevir and in combination or alternation with ribavirin. In certain embodiments, one or more compounds provided herein can be administered in combination or alternation with bocepravir and in combination or alternation with ribavirin.
  • one or more compounds provided herein can be administered in combination or alternation with a protease inhibitor and not in combination or alternation with ribavirin. In certain embodiments, one or more compounds provided herein can be administered in combination or alternation with telaprevir and not in combination or alternation with ribavirin. In certain embodiments, one or more compounds provided herein can be administered in combination or alternation with bocepravir and not in combination or alternation with ribavirin.
  • one or more compounds provided herein can be administered in combination or alternation with an interferon. In certain embodiments, one or more compounds provided herein can be administered in combination or alternation with interferon alfacon-1. In certain embodiments, one or more compounds provided herein can be administered in combination or alternation with interferon alfa-2b. In certain embodiments, one or more compounds provided herein can be administered in combination or alternation with pegylated interferon alpha 2a. In certain embodiments, one or more compounds provided herein can be administered in combination or alternation with pegylated interferon alpha 2b.
  • one or more compounds provided herein can be administered in combination or alternation with an interferon and in combination or alternation with ribavirin. In certain embodiments, one or more compounds provided herein can be administered in combination or alternation with interferon alfacon-1 and in combination or alternation with ribavirin. In certain embodiments, one or more compounds provided herein can be administered in combination or alternation with interferon alfa-2b and in combination or alternation with ribavirin. In certain embodiments, one or more compounds provided herein can be administered in combination or alternation with pegylated interferon alpha 2a and in combination or alternation with ribavirin.
  • one or more compounds provided herein can be administered in combination or alternation with pegylated interferon alpha 2b and in combination or alternation with ribavirin.
  • one or more compounds can be administered in combination or alternation with one or more of the second agents provided herein and not in combination or alternation with ribavirin.
  • one or more compounds provided herein can be administered in combination or alternation with an interferon and not in combination or alternation with ribavirin.
  • one or more compounds provided herein can be administered in combination or alternation with interferon alfacon-land not in combination or alternation with ribavirin.
  • one or more compounds provided herein can be administered in combination or alternation with interferon alfa-2b and not in combination or alternation with ribavirin. In certain embodiments, one or more compounds provided herein can be administered in combination or alternation with pegylated interferon alpha 2a and not in combination or alternation with ribavirin. In certain embodiments, one or more compounds provided herein can be administered in combination or alternation with pegylated interferon alpha 2b and not in combination or alternation with ribavirin.
  • Diastereoisomer 1 Diastereoisomer 2
  • TEA 8.03 mmol
  • the reaction mixture was stirred at 0°C during 30 minutes and was allowed to reach room temperature overnight.
  • the organic layer was dried on Na 2 S0 4 , filtered and concentrated under reduced pressure.
  • the crude was purified by silica gel chromatography (eluent: CH 2 CI 2 /CH 3 CH 2 OH 0 to 10%) and by preparative MS/HPLC to give the expected compounds as a white solid.
  • the expected compound was obtained as impure material. Yellow translucent oil;
  • DiastereoisomeM Diastereoisomer2
  • DiastereoisomeM Diastereoisomer2
  • Huh-7-derived cell line (Zluc) that harbors an HCV genotype lb replicon and a luciferase reporter gene was grown in Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% fetal bovine serum, 2 mM GlutaMAX, 1% MEM nonessential amino acids, 100 IU/mL penicillin, 100 ⁇ g/mL streptomycin, and 0.5 mg/mL Geneticin ® (G418).
  • DMEM Dulbecco's Modified Eagle Medium
  • the inhibition of HCV replication was measured by quantification of photons emitted after mono-oxygenation of 5'-fluoroluciferin to oxyfluoroluciferin by firefly luciferase. For this, media was removed from the plates via gentle tapping. Fifty microliters of ONE-glo luciferase assay reagent was added to each well. The plates were shaken gently for 3 min at room temperature and luminescence was measured on a Victor V 1420 multilabel counter (Perkin Elmer) with a 1 second read time using a 700 nm cut-off filter. The EC50 values were calculated from dose response curves from the resulting best-fit equations determined by Microsoft Excel and XLfit 4.1 software. When screening at two fixed concentrations, the results were expressed as % inhibition at 1 ⁇ and 10 ⁇ .
  • Diastereomer 1 Diastereomer 2
  • Diastereomer 1 Diastereomer 2
  • Diastereomer 1 Diastereomer 2
  • Diastereomer 1 Diastereomer 2
  • Diastereomer 1 Diastereomer 2
  • Diastereomer 1 Compound HCV Replicon Compound HCV Replicon Reference EC50 CC50 Reference EC50 CC50
  • Diastereomer 1 Diastereomer 2
  • Diastereomer 1 Diastereomer 2
  • Diastereomer 1 Diastereomer 2
  • Diastereomer 1 Diastereomer 2
  • Diastereomer 1 Diastereomer 1
  • Diastereomer 1 Diastereomer 2
  • EC so is provided as fo lows: ++++ ⁇ 250 nM, 250 nM ⁇ +++ ⁇ 1 ⁇ , 1 ⁇ ⁇ ++ ⁇ 10 ⁇ , and + > 10 ⁇ CC 5 o is provided as follows: ++ ⁇ 50 ⁇ , + > 50 ⁇
  • HLM Human liver microsome
  • HIM Human intestinal microsome
  • HLS9 Human liver S9 fraction
  • HIS9 Human intestinal S9 fraction
  • WB H Human whole blood
  • WB M Mouse whole blood
  • SGF Simulated gastric fluid
  • SIF Simulated intestinal fluid.
  • Stability in fresh whole blood Stability of compounds were determined in fresh human whole blood with K 2 EDTA as the anticoagulant (stored refrigerated at 2-8°C and used within 7 days of receipt). The experiment was conducted with three replicates for each time point. Whole blood, pre-incubated at 37°C for 10 - 15 minutes, was fortified with a solution of test compound for a final concentration of 0.5 ⁇ and mixed for 30 sec. At intervals (0, 0.5, 1 and 2 hr), three 50- ⁇ aliquots were combined with 200 ⁇ _, (each) of an ice-cold solution of the internal standard (carbutamide 500 ng/mL in acetonitrile).
  • Stability in liver subcellular fractions Stability of compounds were determined in subcellular fractions (microsomes) of human liver in duplicate for each matrix. Pooled liver microsomal proteins (1.0 mg/mL), suspended in incubation buffer (100 mM potassium phosphate, pH 7.4, 5 mM MgCl 2 , and 0.1 mM EDTA), were preincubated for 5 min at 37°C with 10 ⁇ of a test compound from a 10 mM stock solution in DMSO (final DMSO concentration was 0.1%); the reaction was initiated by the addition of NADPH (3 mM final concentration).
  • incubation buffer 100 mM potassium phosphate, pH 7.4, 5 mM MgCl 2 , and 0.1 mM EDTA
  • Huh-7 cells were plated in 1 mL culture medium (DMEM, containing glucose, L-glutamine and sodium pyruvate, 10% FBS, 100 IU/mL penicillin, 100 ⁇ g/mL streptomycin, 2 mM GlutaMAX, 1% MEM nonessential amino acids) at the concentration 0.8, 0.4 and 0.2 million cells per well on 6 well plates for 24, 48 and 72 hr treatment, respectively. Plated cells were incubated overnight at 37°C in an incubator.
  • DMEM containing glucose, L-glutamine and sodium pyruvate
  • FBS 100 IU/mL penicillin
  • streptomycin 100 IU/mL
  • 2 mM GlutaMAX 1% MEM nonessential amino acids
  • FHH fresh human hepatocytes
  • Ms Mouse
  • MsH Mouse hepatocyte.
  • Assay for the release of active metabolite in primary hepatocytes Plates of fresh human and mouse hepatocytes were obtained on ice. The medium was removed and replaced with hepatocyte culture medium (William's E supplemented with penicillin-streptomycin, 1% L-glutamine, 1% insulin-transferrin-selenium and 0.1 ⁇ Dexamethasone (Invitrogen) or with Invitro GRO HI medium complemented with Torpedo antibiotics (Celsis)). Cells were left overnight in an incubator at 37 °C to acclimatize to culture and the medium.
  • Hepatocyte incubations were conducted at a final volume of 0.5 mL hepatocyte culture medium/well (0.8 million cells/well for human and 0.5 million cells/well for mouse; 12 well plate no overlay, collagen coat). Culture medium from overnight incubation of cells was removed and replaced with fresh medium, pre-warmed to 37°C, containing 10 ⁇ of test compound from a stock solution in DMSO (final DMSO concentration was 0.1%). At each specific time point, incubation medium was removed and cell monolayers were carefully washed two times with ice-cold PBS. Following the last wash, all PBS was carefully removed and 1.0 mL of extraction solution (ice-cold 70%> methanol/30%) water) added. Cells were scraped off and suspended in the extraction solution, transferred to 2 mL polypropylene micro fuge tubes and intracellular contents extracted overnight at -20°C.
  • the cellular extracts were prepared by centrifugation at 16,000 x g for 10 min to remove cellular debris. The remaining sample was then dried using a refrigerated centrivap concentrator. Dry extracts were reconstituted in 1000 ⁇ of HPLC- grade water and centrifuged at 16,000 x g for 10 min. Aliquots (100 ⁇ , each) of the supernatant were transferred into a 96 well plate and internal standard (4 ng/mL final concentration) was added as the internal standard (IS) for LC-MS/MS analysis.
  • IS internal standard
  • the incubation time points were 6, 24 and 48 hours for human hepatocytes and 1, 4, 8, 12 and 24 hours for mouse hepatocytes. Results are provided in Table 3 below.
  • Ms Mouse
  • 2'-MeG 2'-methylguanosine
  • 2'-MeGTP 2'- methylguanosine triphosphate
  • test compound at 25 mg/kg in PEG 200 (dose volume 5 mL/kg) was administered to nine CD-I male mice.
  • Five untreated animals were used for the collection of control plasma and liver.
  • Terminal plasma and liver samples were collected from three animals per time point at 4, 12 and 24 hours post dose.
  • Liver specimens were collected from all animals immediately after the incision. Freezing forceps stored in liquid nitrogen were used to freeze the liver before excision.
  • Plasma samples were analyzed for 2'-methylguanosine (2'-MeG) by LC-MS/MS.
  • the internal standard (IS) was 2'-MeG-D3.
  • each plasma sample 50 ⁇ was treated with 500 of 0.2% formic acid in acetonitrile and 20 of the internal standard working solution. After vortexing and centrifugation, 500 ⁇ of the sample extracts were transferred to a new plate, dried under N2 at ⁇ 28°C and reconstituted with 75 ⁇ of 0.2% FA in water.
  • the extracts were chromatographed on an Aquasil C18 column using a gradient system of 0.2% formic acid in water and acetonitrile.
  • the analytes were detected and quantified by tandem mass spectrometry in positive ion mode on an MDS Sciex API5000 equipped with a Turbo Ionspray® interface.
  • the calibration range was 0.500 (LLOQ) to 200 ng/mL in mouse plasma.
  • the corresponding range for molar units is 1.68 to 673 pmol/mL.
  • Liver samples were analyzed for the active species 2'-methylguanosine triphosphate (2'-MeGTP) by LC-MS/MS.
  • 2'-MeGTP levels were assayed by homogenizing (on ice) a known weight of mouse liver with 4X volume of 0.95 M trichloroacetic acid (TCA). Internal standard solution was added to the homogenate followed by neutralization with 20% ammonium hydroxide solution and addition of 500 ⁇ ⁇ 1% formic acid.
  • TCA trichloroacetic acid
  • the tissue samples were extracted by weak anion exchange solid phase extraction (SPE). Post extraction, the eluates were evaporated under nitrogen, followed by reconstitution before injection onto the LC-MS/MS system.
  • the samples were chromatographed on a Luna NH2 column using a gradient system of ammonium acetate (1 mM to 20 mM and pH 8.0 to pH 10.0) in water and acetonitrile (70:30).
  • the analyte was detected and quantified by tandem mass spectrometry in positive ion mode on an API4000 equipped with a Turbo Ionspray® interface.
  • the calibration range was 10 to 10000 pmol/mL in mouse liver homogenate (50 to 50000 pmol/g of mouse liver).

Abstract

L'invention concerne des composés, des compositions et des méthodes pour traiter des infections par Flaviviridae, notamment les infections par le virus de l'hépatite C (VHC). Dans certains modes de réalisation, l'invention concerne des composés et des compositions de dérivés de nucléoside, qui peuvent être administrés soit seuls soit en combinaison avec d'autres agents antiviraux.
EP13725544.4A 2012-05-22 2013-05-21 Promédicaments de 3',5'-phosphate cyclique pour traiter une infection par le virus de l'hépatite c Active EP2852605B1 (fr)

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